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Blanton HL, Barnes RC, McHann MC, Bilbrey JA, Wilkerson JL, Guindon J. Sex differences and the endocannabinoid system in pain. Pharmacol Biochem Behav 2021; 202:173107. [PMID: 33444598 DOI: 10.1016/j.pbb.2021.173107] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 11/30/2020] [Accepted: 12/30/2020] [Indexed: 01/21/2023]
Abstract
Cannabis use has been increasing in recent years, particularly among women, and one of the most common uses of cannabis for medical purposes is pain relief. Pain conditions and response to analgesics have been demonstrated to be influenced by sex, and evidence is emerging that this is also true with cannabinoid-mediated analgesia. In this review we evaluate the preclinical evidence supporting sex differences in cannabinoid pharmacology, as well as emerging evidence from human studies, both clinical and observational. Numerous animal studies have reported sex differences in the antinociceptive response to natural and synthetic cannabinoids that may correlate to sex differences in expression, and function, of endocannabinoid system components. Female rodents have generally been found to be more sensitive to the effects of Δ9-THC. This finding is likely a function of both pharmacokinetic and pharmacodynamics factors including differences in metabolism, differences in cannabinoid receptor expression, and influence of ovarian hormones including estradiol and progesterone. Preclinical evidence supporting direct interactions between sex hormones and the endocannabinoid system may translate to sex differences in response to cannabis and cannabinoid use in men and women. Further research into the role of sex in endocannabinoid system function is critical as we gain a deeper understanding of the impact of the endocannabinoid system in various disease states, including chronic pain.
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Affiliation(s)
- Henry L Blanton
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, United States of America.
| | - Robert C Barnes
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, United States of America
| | - Melissa C McHann
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, United States of America
| | - Joshua A Bilbrey
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, United States of America
| | - Jenny L Wilkerson
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32611, United States of America
| | - Josée Guindon
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, United States of America.
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van Aken MA, Groothuis PG, Panagiotou M, Duin MV, Nap AW, van Rijn TC, Kozicz T, Braat DD, Peeters AB. An objective and automated method for evaluating abdominal hyperalgesia in a rat model for endometriosis. Lab Anim 2019; 54:365-372. [PMID: 31366270 DOI: 10.1177/0023677219856915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Chronic pain and subfertility are the main symptoms of concern in women with endometriosis. In order to find new therapeutic options to suppress the pain, translational animal models are indispensable. We have developed a new automated, experimental setup, with full consideration for animal wellbeing, to determine whether operant behaviour can reveal abdominal hyperalgesia in rats with surgically-induced endometriosis, in order to assess whether abdominal hyperalgesia affect behavioural parameters. Endometriosis was induced by transplantation of uterine fragments in the abdominal cavity. Control groups consisted of sham-operated rats and non-operated rats. We have developed an operant chamber (Skinnerbox) which includes a barrier. The rat can climb the barrier in order to reach the food pellet, increasing in this way the pressure to the abdomen. We show that endometriosis rats collect significantly less sugar pellets when compared with the control rats after the introduction of the barrier. In the Skinnerbox experiment, we showed that in a positive operant setting, the introduction of a barrier results in a contrast of operant behaviour of endometriosis rats and control groups, perchance as a result of abdominal discomfort/hyperalgesia due to surgically-induced endometriosis. This is a promising start for the further development of a refined animal model to monitor abdominal discomfort/hyperalgesia in rats with surgically-induced endometriosis.
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Affiliation(s)
- Mieke Aw van Aken
- Department of Anatomy, Radboud University Medical Centre Nijmegen, The Netherlands.,Department of Gynaecology and Obstetrics, Rijnstate, The Netherlands.,Department of Obstetrics and Gynaecology, Radboud University Medical Centre Nijmegen, The Netherlands
| | | | | | | | - Annemiek W Nap
- Department of Gynaecology and Obstetrics, Rijnstate, The Netherlands
| | - Tineke Cm van Rijn
- Radboud University, Donders Institute for Brain, Cognition and Behaviour, The Netherlands
| | - Tamas Kozicz
- Department of Anatomy, Radboud University Medical Centre Nijmegen, The Netherlands.,Department of Clinical Genomics, Mayo Clinic, USA
| | - Didi Dm Braat
- Department of Obstetrics and Gynaecology, Radboud University Medical Centre Nijmegen, The Netherlands
| | - Ard Bwmm Peeters
- Department of Anatomy, Radboud University Medical Centre Nijmegen, The Netherlands
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Sajjad J, Felice VD, Golubeva AV, Cryan JF, O’Mahony SM. Sex-dependent activity of the spinal excitatory amino acid transporter: Role of estrous cycle. Neuroscience 2016; 333:311-9. [DOI: 10.1016/j.neuroscience.2016.07.036] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 06/28/2016] [Accepted: 07/20/2016] [Indexed: 02/07/2023]
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Marson L, Giamberardino MA, Costantini R, Czakanski P, Wesselmann U. Animal Models for the Study of Female Sexual Dysfunction. Sex Med Rev 2015; 1:108-122. [PMID: 27784584 DOI: 10.1002/smrj.14] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Significant progress has been made in elucidating the physiological and pharmacological mechanisms of female sexual function through preclinical animal research. The continued development of animal models is vital for the understanding and treatment of the many diverse disorders that occur in women. AIM To provide an updated review of the experimental models evaluating female sexual function that may be useful for clinical translation. METHODS Review of English written, peer-reviewed literature, primarily from 2000 to 2012, that described studies on female sexual behavior related to motivation, arousal, physiological monitoring of genital function and urogenital pain. MAIN OUTCOMES MEASURES Analysis of supporting evidence for the suitability of the animal model to provide measurable indices related to desire, arousal, reward, orgasm, and pelvic pain. RESULTS The development of female animal models has provided important insights in the peripheral and central processes regulating sexual function. Behavioral models of sexual desire, motivation, and reward are well developed. Central arousal and orgasmic responses are less well understood, compared with the physiological changes associated with genital arousal. Models of nociception are useful for replicating symptoms and identifying the neurobiological pathways involved. While in some cases translation to women correlates with the findings in animals, the requirement of circulating hormones for sexual receptivity in rodents and the multifactorial nature of women's sexual function requires better designed studies and careful analysis. The current models have studied sexual dysfunction or pelvic pain in isolation; combining these aspects would help to elucidate interactions of the pathophysiology of pain and sexual dysfunction. CONCLUSIONS Basic research in animals has been vital for understanding the anatomy, neurobiology, and physiological mechanisms underlying sexual function and urogenital pain. These models are important for understanding the etiology of female sexual function and for future development of pharmacological treatments for sexual dysfunctions with or without pain. Marson L, Giamberardino MA, Costantini R, Czakanski P, and Wesselmann U. Animal models for the study of female sexual dysfunction. Sex Med Rev 2013;1:108-122.
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Affiliation(s)
- Lesley Marson
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | | | | | - Peter Czakanski
- University of Alabama at Birmingham-Departments of Anesthesiology and Obstetrics & Gynecology, Birmingham, AL, USA
| | - Ursula Wesselmann
- University of Alabama at Birmingham-Departments of Anesthesiology and Neurology, Birmingham, AL, USA
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Iacovides S, Avidon I, Baker F. Does pain vary across the menstrual cycle? A review. Eur J Pain 2015; 19:1389-405. [DOI: 10.1002/ejp.714] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2015] [Indexed: 02/06/2023]
Affiliation(s)
- S. Iacovides
- Wits Dial-a-bed Sleep Laboratory; Brain Function Research Group; School of Physiology; Faculty of Health Sciences; University of the Witwatersrand; Johannesburg South Africa
| | - I. Avidon
- Exercise Physiology Laboratory; School of Physiology; Faculty of Health Sciences; University of the Witwatersrand; Johannesburg South Africa
| | - F.C. Baker
- Wits Dial-a-bed Sleep Laboratory; Brain Function Research Group; School of Physiology; Faculty of Health Sciences; University of the Witwatersrand; Johannesburg South Africa
- Human Sleep Research Program; SRI International; San Francisco USA
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6
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Meerts SH, Strnad HK, Schairer RS. Paced mating behavior is affected by clitoral-vaginocervical lidocaine application in combination with sexual experience. Physiol Behav 2015; 140:222-9. [DOI: 10.1016/j.physbeh.2014.12.043] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 12/23/2014] [Accepted: 12/24/2014] [Indexed: 11/25/2022]
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O'Mahony SM, Felice VD, Nally K, Savignac HM, Claesson MJ, Scully P, Woznicki J, Hyland NP, Shanahan F, Quigley EM, Marchesi JR, O'Toole PW, Dinan TG, Cryan JF. Disturbance of the gut microbiota in early-life selectively affects visceral pain in adulthood without impacting cognitive or anxiety-related behaviors in male rats. Neuroscience 2014; 277:885-901. [PMID: 25088912 DOI: 10.1016/j.neuroscience.2014.07.054] [Citation(s) in RCA: 202] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Revised: 06/19/2014] [Accepted: 07/15/2014] [Indexed: 02/08/2023]
Abstract
Disruption of bacterial colonization during the early postnatal period is increasingly being linked to adverse health outcomes. Indeed, there is a growing appreciation that the gut microbiota plays a role in neurodevelopment. However, there is a paucity of information on the consequences of early-life manipulations of the gut microbiota on behavior. To this end we administered an antibiotic (vancomycin) from postnatal days 4-13 to male rat pups and assessed behavioral and physiological measures across all aspects of the brain-gut axis. In addition, we sought to confirm and expand the effects of early-life antibiotic treatment using a different antibiotic strategy (a cocktail of pimaricin, bacitracin, neomycin; orally) during the same time period in both female and male rat pups. Vancomycin significantly altered the microbiota, which was restored to control levels by 8 weeks of age. Notably, vancomycin-treated animals displayed visceral hypersensitivity in adulthood without any significant effect on anxiety responses as assessed in the elevated plus maze or open field tests. Moreover, cognitive performance in the Morris water maze was not affected by early-life dysbiosis. Immune and stress-related physiological responses were equally unaffected. The early-life antibiotic-induced visceral hypersensitivity was also observed in male rats given the antibiotic cocktail. Both treatments did not alter visceral pain perception in female rats. Changes in visceral pain perception in males were paralleled by distinct decreases in the transient receptor potential cation channel subfamily V member 1, the α-2A adrenergic receptor and cholecystokinin B receptor. In conclusion, a temporary disruption of the gut microbiota in early-life results in very specific and long-lasting changes in visceral sensitivity in male rats, a hallmark of stress-related functional disorders of the brain-gut axis such as irritable bowel disorder.
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Affiliation(s)
- S M O'Mahony
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - V D Felice
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - K Nally
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Biochemistry, University College Cork, Cork, Ireland
| | - H M Savignac
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - M J Claesson
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Microbiology, University College Cork, Cork, Ireland
| | - P Scully
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - J Woznicki
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - N P Hyland
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Pharmacology & Therapeutics, University College Cork, Cork, Ireland
| | - F Shanahan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Medicine, University College Cork, Cork, Ireland
| | - E M Quigley
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - J R Marchesi
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - P W O'Toole
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Microbiology, University College Cork, Cork, Ireland
| | - T G Dinan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Psychiatry, University College Cork, Cork, Ireland
| | - J F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
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Meleine M, Matricon J. Gender-related differences in irritable bowel syndrome: Potential mechanisms of sex hormones. World J Gastroenterol 2014; 20:6725-6743. [PMID: 24944465 PMCID: PMC4051914 DOI: 10.3748/wjg.v20.i22.6725] [Citation(s) in RCA: 148] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 02/08/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
According to epidemiological studies, twice as many women as men are affected by irritable bowel syndrome (IBS) in western countries, suggesting a role for sex hormones in IBS pathophysiology. Despite growing evidence about the implications of sex hormones in IBS symptom modulation, data on mechanisms by which they influence disease development are sparse. This review aims to determine the state of knowledge about the role of sex hormones in sensorimotor dysfunctions and to address the possible interplay of sex hormones with common risk factors associated with IBS. The scientific bibliography was searched using the following keywords: irritable bowel syndrome, sex, gender, ovarian hormone, estradiol, progesterone, testosterone, symptoms, pain, sensitivity, motility, permeability, stress, immune system, brain activity, spinal, supraspinal, imaging. Ovarian hormones variations along the menstrual cycle affect sensorimotor gastrointestinal function in both healthy and IBS populations. They can modulate pain processing by interacting with neuromodulator systems and the emotional system responsible for visceral pain perception. These hormones can also modulate the susceptibility to stress, which is a pivotal factor in IBS occurrence and symptom severity. For instance, estrogen-dependent hyper-responsiveness to stress can promote immune activation or impairments of gut barrier function. In conclusion, whereas it is important to keep in mind that ovarian hormones cannot be considered as a causal factor of IBS, they arguably modulate IBS onset and symptomatology. However, our understanding of the underlying mechanisms remains limited and studies assessing the link between IBS symptoms and ovarian hormone levels are needed to improve our knowledge of the disease evolution with regard to gender. Further studies assessing the role of male hormones are also needed to understand fully the role of sex hormones in IBS. Finally, investigation of brain-gut interactions is critical to decipher how stress, ovarian hormones, and female brain processing of pain can translate into gut dysfunctions.
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Traub RJ, Ji Y. Sex differences and hormonal modulation of deep tissue pain. Front Neuroendocrinol 2013; 34:350-66. [PMID: 23872333 PMCID: PMC3830473 DOI: 10.1016/j.yfrne.2013.07.002] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 07/08/2013] [Accepted: 07/09/2013] [Indexed: 12/11/2022]
Abstract
Women disproportionately suffer from many deep tissue pain conditions. Experimental studies show that women have lower pain thresholds, higher pain ratings and less tolerance to a range of painful stimuli. Most clinical and epidemiological reports suggest female gonadal hormones modulate pain for some, but not all, conditions. Similarly, animal studies support greater nociceptive sensitivity in females in many deep tissue pain models. Gonadal hormones modulate responses in primary afferents, dorsal horn neurons and supraspinal sites, but the direction of modulation is variable. This review will examine sex differences in deep tissue pain in humans and animals focusing on the role of gonadal hormones (mainly estradiol) as an underlying component of the modulation of pain sensitivity.
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Affiliation(s)
- Richard J Traub
- Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, 650 W. Baltimore St., 8 South, Baltimore, MD 21201, USA; Program in Neuroscience, University of Maryland Baltimore, Baltimore, MD 21201, USA; Center for Pain Studies, University of Maryland Baltimore, Baltimore, MD 21201, USA.
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10
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Sprouted innervation into uterine transplants contributes to the development of hyperalgesia in a rat model of endometriosis. PLoS One 2012; 7:e31758. [PMID: 22363725 PMCID: PMC3283674 DOI: 10.1371/journal.pone.0031758] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Accepted: 01/18/2012] [Indexed: 01/30/2023] Open
Abstract
Endometriosis is an enigmatic painful disorder whose pain symptoms remain difficult to alleviate in large part because the disorder is defined by extrauteral endometrial growths whose contribution to pain is poorly understood. A rat model (ENDO) involves autotransplanting on abdominal arteries uterine segments that grow into vascularized cysts that become innervated with sensory and sympathetic fibers. ENDO rats exhibit vaginal hyperalgesia. We used behavioral, physiological, and immunohistochemical methods to test the hypothesis that cyst innervation contributes to the development of this hyperalgesia after transplant. Rudimentary sensory and sympathetic innervation appeared in the cysts at two weeks, sprouted further and more densely into the cyst wall by four weeks, and matured by six weeks post-transplant. Sensory fibers became abnormally functionally active between two and three weeks post-transplant, remaining active thereafter. Vaginal hyperalgesia became significant between four and five weeks post-transplant, and stabilized after six to eight weeks. Removing cysts before they acquired functional innervation prevented vaginal hyperalgesia from developing, whereas sham cyst removal did not. Thus, abnormally-active innervation of ectopic growths occurs before hyperalgesia develops, supporting the hypothesis. These findings suggest that painful endometriosis can be classified as a mixed inflammatory/neuropathic pain condition, which opens new avenues for pain relief. The findings also have implications beyond endometriosis by suggesting that functionality of any transplanted tissue can be influenced by the innervation it acquires.
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Women and visceral pain: Are the reproductive organs the main protagonists? Mini-review at the occasion of the “European Week Against Pain in Women 2007”. Eur J Pain 2012; 12:257-60. [DOI: 10.1016/j.ejpain.2007.11.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2007] [Accepted: 11/27/2007] [Indexed: 12/28/2022]
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Frye CA. Progesterone attenuates depressive behavior of younger and older adult C57/BL6, wildtype, and progesterone receptor knockout mice. Pharmacol Biochem Behav 2011; 99:525-31. [PMID: 21669220 PMCID: PMC3376530 DOI: 10.1016/j.pbb.2011.05.024] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2010] [Revised: 05/19/2011] [Accepted: 05/22/2011] [Indexed: 12/29/2022]
Abstract
Progesterone may have actions independent of intracellular progestin receptors (PRs) to influence depressive behavior. To investigate this, we examined effects of progesterone (P; 10mg/kg, SC) on the depressive behavior of mice in the forced swim test (FST). In Experiment 1, subjects were 4 to 6 months old, intact or ovariectomized (OVX) female and intact or gonadectomized (GDX) male, C57/BL6 mice. Progesterone reduced depressive behavior of young diestrous and OVX mice but male mice were impervious to effects of P. In Experiment 2, subjects were intact aged (20-28 months old) C57/BL6 female and male mice. Progesterone reduced depressive behavior of aged female and male C57/BL6 mice, albeit effects were greater among males. In Experiment 3, effects of P were examined in 4 to 6 months old, gonadally-intact, female and male mice that were wildtype or PR knockouts (PRKOs). Progesterone decreased depressive behavior of young adult, wildtype and PRKO mice, which showed greater immobility than did their wildtype counterparts. In Experiment 4, subjects were 18-24 months old wildtype or PRKO mice (Exp 4). Progesterone decreased immobility among wildtype and PRKO mice (which were not different in terms of their baseline depressive behavior). Together these data demonstrate that P decreases depressive behavior of young and older adult C57/BL6, wildtype and PRKO mice, which suggest that acute anti-depressant effects of P may occur independent of actions at "classic" PRs.
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Affiliation(s)
- Cheryl A Frye
- Department of Psychology, The University at Albany-SUNY, Albany, NY 12222, USA.
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Ji Y, Tang B, Traub RJ. Spinal estrogen receptor alpha mediates estradiol-induced pronociception in a visceral pain model in the rat. Pain 2011; 152:1182-1191. [PMID: 21392887 PMCID: PMC3079062 DOI: 10.1016/j.pain.2011.01.046] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2010] [Revised: 01/21/2011] [Accepted: 01/24/2011] [Indexed: 02/07/2023]
Abstract
We previously reported that 17β-estradiol (E2) is pronociceptive in a visceral pain model in the rat. Subcutaneously (s.c.) administered E2 reversed the decrease in the colorectal distention (CRD)-evoked visceromotor response produced by ovariectomy (OVx) and CRD-induced nociceptive responses were greater in proestrous rats compared with met/diestrous rats. The site of action, the type of estrogen receptors activated, and the possible intracellular signaling pathway involved are yet to be established. In the present study, intrathecal (i.t.) E2 administered to OVx rats mimicked the effects of s.c. E2, suggesting that spinal estrogen receptors are involved. This is further supported by the observations that the anti-estrogen ICI 182,780 injected i.t. in intact female rats significantly decreased the visceromotor response to CRD, the response of colonic afferents was not affected by OVx, and colonic afferents did not label for estrogen receptor α (ERα). The ERα selective agonist, 4,4',4''-[4-propyl-(1H)-pyrazole-1,3,5-triyl]tris-phenol (PPT; s.c. or i.t.) facilitated the visceromotor response similar to E2, suggesting ERα activation is involved in mediating the pronociceptive effect of E2. PPT (s.c. or i.t.) increased the response of spinal dorsal horn neurons to CRD, indicating a spinal site of action. In addition, s.c. E2 or PPT increased CRD-induced spinal extracellular signal-regulated kinase (ERK) phosphorylation that was not observed in OVx rats and a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor blocked facilitation of the visceromotor response by PPT. Taken together, the present study demonstrates that spinal ERα mediates the pronociceptive effect of E2 on visceral signal processing through activation of the MAPK pathway.
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Affiliation(s)
- Yaping Ji
- Department of Neural and Pain Sciences, University of Maryland Dental School, Baltimore, MD, USA
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Giuliano F, Pfaus J, Balasubramanian S, Hedlund P, Hisasue SI, Marson L, Wallen K. Experimental Models for the Study of Female and Male Sexual Function. J Sex Med 2010; 7:2970-95. [DOI: 10.1111/j.1743-6109.2010.01960.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Botelho AP, Gameiro GH, Tuma CEDSN, Marcondes FK, de Arruda Veiga MCF. The effects of acute restraint stress on nociceptive responses evoked by the injection of formalin into the temporomandibular joint of female rats. Stress 2010; 13:269-75. [PMID: 20392197 DOI: 10.3109/10253890903362645] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The temporomandibular joint (TMJ) formalin test was used to evaluate the effects of acute restraint stress on the nociceptive behavioral responses of female rats during proestrus and estrus phases of the estrous cycle. Rats were subjected to one session of restraint stress (15, 30 min or 1 h). They were then either immediately killed to allow the collection of blood for hormonal radioimmunoassay determinations or subjected to TMJ formalin test to evaluate nociception. All stress protocols significantly raised the plasma concentrations of corticosterone. The performance of rats subjected to 15 and 30 min of restraint stress was similar to that of control rats, whereas rats that were stressed for 1 h showed a decrease in nociceptive responses, during both proestrus and estrus phases. The stress-induced analgesia (SIA) was greater in the proestrus phase. To evaluate the role of kappa-opioid receptors, the selective receptor kappa-opioid antagonist nor-binaltorphimine (nor-BNI; 200 microg or saline) was injected into the TMJ 24 h prior to the 1 h stress period and the TMJ formalin test. The local administration of nor-BNI partially reversed the SIA during the proestrus phase. These findings suggest that (1) acute stress for 1 h can produce analgesia both during proestrus and estrus phases; this effect is greater during the proestrus phase and (2) kappa-opioid receptor activation is involved in the SIA observed in the proestrus phase.
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Affiliation(s)
- Ana Paula Botelho
- Laboratory of Orofacial Pain, Department of Physiological Sciences, Piracicaba Dental School, University of Campinas-UNICAMP, Piracicaba, Sao Paulo, Brazil
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Peng HY, Chen GD, Lai CY, Hsieh MC, Hsu HH, Wu HC, Lin TB. PI3K modulates estrogen-dependent facilitation of colon-to-urethra cross-organ reflex sensitization in ovariectomized female rats. J Neurochem 2010; 113:54-66. [DOI: 10.1111/j.1471-4159.2010.06577.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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McAllister SL, McGinty KA, Resuehr D, Berkley KJ. Endometriosis-induced vaginal hyperalgesia in the rat: role of the ectopic growths and their innervation. Pain 2009; 147:255-64. [PMID: 19819623 DOI: 10.1016/j.pain.2009.09.022] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2009] [Revised: 08/19/2009] [Accepted: 09/21/2009] [Indexed: 12/27/2022]
Abstract
Endometriosis is a painful disorder defined by extrauteral endometrial growths whose contribution to pain symptoms is poorly understood. Endometriosis is created in rats by autotransplanting on abdominal arteries pieces of either uterus (ENDO), which form cysts, or fat (shamENDO), which do not form cysts. ENDO, but not shamENDO induces vaginal hyperalgesia. We tested the hypothesis that the cysts are necessary to maintain vaginal hyperalgesia by assessing the effect of surgically removing them. Complete-cyst-removal eliminated ENDO-induced vaginal hyperalgesia up to 4 months post-operatively. Sham-cyst-removal in ENDO rats, in which cysts were not removed, or partial cyst-removal increased the ENDO-induced hyperalgesia. The decreases and increases both took 3-6 weeks to develop. Changes in ENDO-induced hyperalgesia did not occur in a control group of ENDO rats who had no surgery after ENDO. In a double-surgery control group, neither shamENDO surgery nor a subsequent sham surgery that mimicked "removal" of non-existent cysts influenced vaginal nociception. In a no-surgery control group, vaginal nociception remained stable for >6 months. The increases in ENDO-induced hyperalgesia produced by the sham-cyst-removal surgery were smaller in proestrus than in other estrous stages. During the other stages (but not during proestrus), sympathetic innervation of the cysts increased. These results suggest that maintenance of ENDO-induced vaginal hyperalgesia requires continued presence of at least some ectopic endometrial tissue, and that surgical treatment that fails to remove ectopic endometrial tissue can exacerbate the hyperalgesia, possibly due in part to an increase in the cysts' sympathetic innervation.
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Affiliation(s)
- Stacy L McAllister
- Program in Neuroscience, Florida State University, Tallahassee, FL 32306-4301, USA
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Reed WR, Chadha HK, Hubscher CH. Effects of 17beta-estradiol on responses of viscerosomatic convergent thalamic neurons in the ovariectomized female rat. J Neurophysiol 2009; 102:1062-74. [PMID: 19553492 DOI: 10.1152/jn.00165.2009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Ovarian hormones have been shown to exert multiple effects on CNS function and viscerosomatic convergent activity. Ovariectomized (OVX) female rats were used in the present study to examine the long-term effects of proestrus levels of 17beta-estradiol (EB) delivered by a 60-day time-released subcutaneous pellet on the response properties of viscerosomatic convergent thalamic neurons. In addition, avoidance thresholds to mechanical stimulation for one of the convergent somatic territories, the trunk, was assessed using an electro-von Frey anesthesiometer before and at the end of the 6-wk post-OVX/implant period prior to the terminal electrophysiological experiments, which were done under urethane anesthesia. Rats implanted with an EB-containing pellet, relative to placebo controls, demonstrated 1) altered thalamic response frequencies and thresholds for cervix and vaginal but not colon stimulation; 2) some response variations for just the lateral group of thalamic subnuclei; and 3) altered thalamic response frequencies and thresholds for trunk stimulation. Thalamic response thresholds for trunk pressure in EB versus placebo rats were consistent with the avoidance thresholds obtained from the same groups. In addition, EB replacement affected visceral and somatic thresholds in opposite ways (i.e., reproductive-related structures were less sensitive to pressure, whereas somatic regions showed increased sensitivity). These results have obvious reproductive advantages (i.e., decreased reproductive organ sensitivity for copulation and increased trunk sensitivity for lordosis posturing), as well as possible clinical implications in women suffering from chronic pelvic pain syndromes and/or neuropathic pain.
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Affiliation(s)
- William R Reed
- Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA
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Heitkemper MM, Chang L. Do fluctuations in ovarian hormones affect gastrointestinal symptoms in women with irritable bowel syndrome? GENDER MEDICINE 2009; 6 Suppl 2:152-67. [PMID: 19406367 PMCID: PMC3322543 DOI: 10.1016/j.genm.2009.03.004] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Accepted: 10/27/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND An increase in gastrointestinal (GI) symptoms, including bowel discomfort, abdominal pain/discomfort, bloating, and alterations in bowel patterns, has been reported during premenses and menses menstrual cycle phases and the perimenopause period in women with and without irritable bowel syndrome (IBS). OBJECTIVE This article reviews the literature related to one possible physiological mechanism-declining or low ovarian hormone levels--that may underlie the occurrence or exacerbations of abdominal pain/discomfort at times of low ovarian hormones (menses, menopause) in women with or without IBS. METHODS To identify English-only review and data-based articles, PubMed was searched between January 1980 and September 2008 using the following terms: irritable bowel syndrome, functional gastrointestinal disorders, gastrointestinal motility, immune, pain, hyperalgesia, menstrual cycle, menopause, pregnancy, estrogen, estradiol (E(2)), and progesterone. Studies in animals and in humans were included; drug trials were excluded. RESULTS From our review of the literature, 18 papers were identified that were related either to the mechanisms accounting for menstrual cycle fluctuations (n = 12) or to the impact of menopausal status on symptoms of IBS (n = 6). One study reported that visceral pain sensitivity was significantly higher during menses than at other menstrual cycle phases in women with IBS (P < 0.05). Other menstrual cycle phase-linked symptoms, dysmenorrheal symptoms (cramping pain) in particular, were more intense in women with IBS. Animal studies have shed some light on the relationship of ovarian hormones to GI sensorimotor function. CONCLUSION The increase in GI symptoms around the time of menses and early menopause occurs at times of declining or low ovarian hormones, suggesting that estrogen and progesterone withdrawal may contribute either directly or indirectly. This review highlights the need for confirmatory preclinical and clinical studies to unravel the role of ovarian hormones in women with IBS.
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Affiliation(s)
- Margaret M Heitkemper
- Department of Biobehavioral Nursing and Health Systems, University of Washington, Seattle, Washington 98125-7266, USA.
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Walf AA, Paris JJ, Frye CA. Nociceptive and anxiety-like behavior in reproductively competent and reproductively senescent middle-aged rats. GENDER MEDICINE 2009; 6 Suppl 2:235-46. [PMID: 19406372 PMCID: PMC2860272 DOI: 10.1016/j.genm.2009.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Accepted: 12/17/2008] [Indexed: 01/12/2023]
Abstract
BACKGROUND Changes in levels of estradiol and progesterone that occur with the transition to reproductive senescence may influence nociception or affect. OBJECTIVE To ascertain whether nociceptive and affective processes change with reproductive senescence, this study examined pain and anxiety-like behaviors in middle-aged female rats that were reproductively competent, transitioning to reproductive senescence, or reproductively senescent. METHODS Middle-aged (12-14 months old) female rats (N = 46) were tested in the following tasks to assess pain and anxiety-like behavior: tail flick, elevated plus maze, elevated zero maze, mirror maze, Vogel punished drinking, and defensive burying. For the tail-flick task, the latency for rats to move their tail from a heat source, as an indication of pain sensitivity, was determined. In the elevated plus and elevated zero mazes, the time spent on the open arms or quadrants, respectively, were determined as measures of reduced anxiety behavior. In the mirror maze, the time spent in the mirrored portion of the chamber was used as an indicator of anxiety-like responding. In the Vogel task, the number of punished licks made was determined as a measure of reduced anxiety-like behavior. In the defensive burying task, the duration spent by rats burying an electrified prod postfootshock was utilized as an index of anxietylike responding. All rats were experimentally naive, retired breeders from our colony and had not had a litter or been lactating for 1 to 4 weeks before behavioral testing. RESULTS Although tail-flick latencies were not significantly different among rats that were reproductively competent or senescent, reproductively competent rats had less anxiety-like behavior in the elevated plus maze (more time spent on the open arms: F(2,43) = 5.93; P < 0.01), elevated zero maze (more time spent on the open quadrants: F(2,43) = 4.62; P = 0.01), and Vogel punished drinking task (more punished licks made: F(2,43) = 3.76; P = 0.03). There were no statistically significant differences in the mirror maze and defensive burying task. CONCLUSION In this study of adult female rats, nociceptive behavior did not vary significantly with reproductive senescence, but anxiety-like behavior of rats did.
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Affiliation(s)
- Alicia A. Walf
- Department of Psychology, The University at Albany-SUNY, Albany, New York
| | - Jason J. Paris
- Department of Psychology, The University at Albany-SUNY, Albany, New York
| | - Cheryl A. Frye
- Department of Psychology, The University at Albany-SUNY, Albany, New York
- Department of Biological Sciences, The University at Albany-SUNY, Albany, New York
- Center for Neuroscience, The University at Albany-SUNY, Albany, New York
- Center for Life Sciences Research, The University at Albany-SUNY, Albany, New York
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Chadha HK, Armstrong JE, Mower GD, Hubscher CH. Effects of surgical induction of endometriosis on response properties of preoptic area neurons in rats. Brain Res 2008; 1246:101-10. [PMID: 18955036 DOI: 10.1016/j.brainres.2008.10.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2008] [Revised: 09/22/2008] [Accepted: 10/02/2008] [Indexed: 10/24/2022]
Abstract
Subfertility and severe pelvic pains are symptoms associated with endometriosis (ENDO), a common condition among women that is characterized by the growth of the uterine endometrium on the surface of organs within the pelvic region and abdominal cavity. The contribution of the CNS to symptoms associated with ENDO is not known. In the present study, the preoptic area (POA) of the hypothalamus was investigated, as this region of the forebrain is known to play an important role in the neuroendocrine control of the reproductive cycle, mating behavior, and antinociception. Female rats were either induced for ENDO by autotransplantation of uterine tissue (n=20) or uterine fat for surgical sham controls (n=11). Terminal extracellular electrophysiological recordings (urethane anesthesia) were conducted in the POA six weeks post-ENDO induction when the rats were in either the proestrus or metestrus stages of their estrous cycle. Significant differences were found between the ENDO versus SHAM groups of animals for the proportion of inhibitory responses as well as the percentage of neurons responding to stimulation of the abdominal branches of the vagus, which innervates portions of the female reproductive tract, including the ovaries. The endometriotic cysts were found to be significantly larger in proestrus rats (stage when hormones are elevated). These data demonstrate that the responses of POA neurons are influenced by the presence of endometriotic cysts in the abdominal cavity. Since the POA is known to be part of the neural circuitries that mediate nociception and fertility, any deviation from its normal activity under ENDO conditions could contribute to the constellation of symptoms that ensue.
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Affiliation(s)
- Harpreet K Chadha
- Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY 40292, USA
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Peng HY, Huang PC, Liao JM, Tung KC, Lee SD, Cheng CL, Shyu JC, Lai CY, Chen GD, Lin TB. Estrous cycle variation of TRPV1-mediated cross-organ sensitization between uterus and NMDA-dependent pelvic-urethra reflex activity. Am J Physiol Endocrinol Metab 2008; 295:E559-68. [PMID: 18577691 DOI: 10.1152/ajpendo.90289.2008] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cross-organ sensitization between the uterus and the lower urinary tract (LUT) underlies the high concurrence of pelvic pain syndrome and LUT dysfunctions, and yet the role of gonadal steroids is still unknown. We tested the hypothesis that cross-organ sensitization on pelvic-urethra reflex activity caused by uterine capsaicin instillation is estrous cycle dependent. When compared with the baseline reflex activity (1.00 +/- 0.00 spikes/stimulation), uterine capsaicin instillation significantly increased reflex activity (45.42 +/- 9.13 spikes/stimulation, P < 0.01, n = 7) that was corroborated by an increase in phosphorylated NMDA NR2B (P < 0.05, n = 4) but not NR2A subunit (P > 0.05, n = 4) expression. Both intrauterine pretreatment with capsazepine (5.02 +/- 2.11 spikes/stimulation, P < 0.01, n = 7) and an intrathecal injection of AP5 (3.21 +/- 0.83 spikes/stimulation, P < 0.01, n = 7) abolished the capsaicin-induced cross-organ sensitization and the increment in the phosphorylated NR2B level (P < 0.05, n = 4). The degrees of the cross-organ sensitization increased in a dose-dependent manner with the concentration of instilled capsaicin from 100 to 300 microM in both the proestrus and metestrus stages, whereas they weakened when the concentrations were higher than 1,000 microM. Moreover, the cross-organ sensitization caused by the uterine capsaicin instillation increased significantly in the rats during the proestrus stage when compared with the metestrus stage (P < 0.01, n = 7). These results suggest that estrogen levels might modulate the cross-organ sensitization between the uterus and the urethra and underlie the high concurrence of pelvic pain syndrome and LUT dysfunctions.
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Affiliation(s)
- Hsien-Yu Peng
- Dept. of Physiology, College of Medicine, Chung-Shan Medical University, Taichung, Taiwan 40201
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Activation of Somatosensory Afferents Elicit Changes in Vaginal Blood Flow and the Urethrogenital Reflex Via Autonomic Efferents. J Urol 2008; 180:1167-72. [DOI: 10.1016/j.juro.2008.04.139] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2007] [Indexed: 01/04/2023]
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Tang B, Ji Y, Traub RJ. Estrogen alters spinal NMDA receptor activity via a PKA signaling pathway in a visceral pain model in the rat. Pain 2008; 137:540-549. [PMID: 18068901 PMCID: PMC2543943 DOI: 10.1016/j.pain.2007.10.017] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2007] [Revised: 09/12/2007] [Accepted: 10/15/2007] [Indexed: 01/24/2023]
Abstract
Pain symptoms in several chronic pain disorders in women, including irritable bowel syndrome, fluctuate with the menstrual cycle suggesting a gonadal hormone component. In female rats, estrogens modulate visceral sensitivity although the underlying mechanism(s) are unknown. In the present study the effects of 17-beta estradiol on N-methyl-D-aspartate (NMDA) receptor signaling of colorectal nociceptive processing in the spinal cord were examined. Estrogen receptor alpha and the NR1 subunit of the NMDA receptor are co-expressed in dorsal horn neurons, supporting a direct action of estradiol on NMDA receptors. Intrathecal administration of the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (APV) dose-dependently attenuated the visceromotor response with greater potency in ovariectomized (OVx) rats compared to OVx with estradiol replacement (E2) rats. Estradiol significantly increased protein expression of NR1 in the lumbosacral spinal cord compared to OVx rats. Colorectal distention significantly increased phosphorylation of NR1ser-897, a PKA phosphorylation site on the NR1 subunit in E2, but not OVx rats. Intrathecal administration of a PKA inhibitor significantly attenuated the visceromotor response, decreased NR1 phosphorylation and increased the potency of APV to attenuate the visceromotor response compared to vehicle-treated E2 rats. These data suggest that estradiol increases spinal processing of visceral nociception by increasing NMDA receptor NR1 subunit expression and increasing site-specific receptor phosphorylation on the NR1 subunit contributing to an increase in NMDA receptor activity.
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Affiliation(s)
- Bin Tang
- Department of Biomedical Sciences, Research Center for Neuroendocrine Influence on Pain, University of Maryland Dental School, 7 South, 650 W. Baltimore, St. Baltimore, MD 21201, USA
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26
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Heitkemper M, Jarrett M. Irritable bowel syndrome: does gender matter? J Psychosom Res 2008; 64:583-7. [PMID: 18501258 DOI: 10.1016/j.jpsychores.2008.02.020] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2007] [Revised: 02/05/2008] [Accepted: 02/07/2008] [Indexed: 02/07/2023]
Abstract
In industrialized parts of the world, women seek health care services for irritable bowel syndrome (IBS) more frequently than men. The role of gender in IBS is likely multifactorial involving inherent physiological differences in gonadal hormones, stress reactivity, and inflammatory responses, as well as sociocultural differences in response to pain and/or bowel pattern changes. This mini-review in particular addresses gender differences in visceral sensitivity, motility, and autonomic nervous system balance as potential factors contributing to gender differences in IBS presentation.
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Affiliation(s)
- Margaret Heitkemper
- Department of Biobehavioral Nursing and Health Systems, University of Washington, Seattle, WA 98195, USA.
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Liu B, Tong C, Eisenach JC. Pregnancy increases excitability of mechanosensitive afferents innervating the uterine cervix. Anesthesiology 2008; 108:1087-92. [PMID: 18497610 PMCID: PMC3876482 DOI: 10.1097/aln.0b013e31817302e0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Labor pain derives primarily from stimulation of afferents innervating the uterine cervix and lower uterine segment. The authors have previously shown that the excitability of these afferents is regulated by sex hormones and test in this study whether pregnancy also alters their excitability. METHODS After animal care committee approval, Sprague-Dawley rats (nonpregnant, pregnant days 17 and 21) were anesthetized, and two metal rods were placed through the cervix for distension. The right hypogastric nerve was dissected and carefully teased until recording from a single unit was obtained. Spontaneous activity and the response to a graded distension (20-80 g) were recorded for off-line analysis. RESULTS A total of 151 fiber units were recorded. Pregnancy was associated with an increase in spontaneous nerve activity in the absence of a mechanical stimulus (median of 0.98 and 1.56 Hz from pregnant days 17 and 21, respectively, compared with 0.45 Hz in nonpregnant; P < 0.01). The proportion of fibers responding to the weakest stimulus (20 g) was significantly greater in pregnant than in nonpregnant animals. The response to graded distension differed significantly among groups, with day 21 > day 17 > nonpregnant. CONCLUSIONS Afferents that innervate the uterine cervix sprout into this tissue during late pregnancy, and estrogen increases excitability of these mechanosensitive afferents. Here, the authors show that excitability also increases during pregnancy. These data suggest that, close to the onset of labor, there is an increased input to the spinal cord from cervical distension and an increased depolarization of afferent terminals in the cervix, effects that could influence pain and the progress of labor.
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Berkley KJ, McAllister SL, Accius BE, Winnard KP. Endometriosis-induced vaginal hyperalgesia in the rat: effect of estropause, ovariectomy, and estradiol replacement. Pain 2007; 132 Suppl 1:S150-S159. [PMID: 17959309 PMCID: PMC2175176 DOI: 10.1016/j.pain.2007.09.022] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2007] [Revised: 09/13/2007] [Accepted: 09/24/2007] [Indexed: 11/23/2022]
Abstract
Endometriosis (ENDO) is a painful disorder defined by extrauteral endometrial growths. It is created in rats by autotransplanting pieces of uterus (which form cysts), or, for shamENDO, fat (no cysts). ENDO induces vaginal hyperalgesia, likely via central sensitization. The severity of this hyperalgesia correlates with estradiol levels during the estrous cycle, suggesting the hyperalgesia is estradiol-modulated. If so, then hyperalgesic severity should track estradiol changes during reproductive senescence (estropause) when estradiol levels initially decrease, then increase. Using psychophysical methods to assess vaginal nociception, we found that the severity of ENDO-induced hyperalgesia paralleled estradiol changes during estropause: hyperalgesia first decreased, then returned. Furthermore, the return occurred regardless of the presence of the cysts (excised in some rats). This finding provides further support for ENDO's likely centrally-mediated effects. Additionally, the results suggest that elimination of estradiol via ovariectomy (OVX) should alleviate ENDO-induced hyperalgesia and estradiol replacement should restore it. However, in healthy and shamENDO rats, OVX produces a vaginal hyperalgesia that is alleviated by estradiol, likely via estradiol's peripheral influences on the vagina. Hence, we tested the hypothesis that OVX in ENDO rats would trigger a different type of vaginal hyperalgesia dependent on the loss of estradiol. We predicted that the opposing influences of estradiol on ENDO- and OVX-induced hyperalgesia would cancel each other. As predicted, OVX had no effect on ENDO-induced hyperalgesia and estradiol replacement alleviated it. These results suggest that, in intact rats, ENDO-induced vaginal hyperalgesia is exacerbated by estradiol, and that different mechanisms underlie ENDO-induced versus OVX-induced vaginal hyperalgesia.
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Affiliation(s)
- Karen J Berkley
- Program in Neuroscience, Eppes Hall, Copeland Street, Florida State University, Tallahassee, FL 32306-1270, USA
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29
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Nagabukuro H, Berkley KJ. Influence of endometriosis on visceromotor and cardiovascular responses induced by vaginal distention in the rat. Pain 2007; 132 Suppl 1:S96-S103. [PMID: 17544211 PMCID: PMC2323582 DOI: 10.1016/j.pain.2007.04.039] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2007] [Revised: 04/20/2007] [Accepted: 04/30/2007] [Indexed: 11/27/2022]
Abstract
This study examined pseudoaffective responses elicited by vaginal distention in urethane-anesthetized rats, and tested hypotheses that responses would be increased by endometriosis (ENDO) and vary with the estrous cycle. Three groups were studied: ENDO, shamENDO, and Naive. ENDO was induced by autotransplanting small pieces of uterine horn (or, for shamENDO, fat) on mesenteric arteries. Ten weeks later, rats in proestrus or metestrus were anesthetized with urethane. Distendable latex balloons were inserted into the vaginal canal. While an increasing series of vaginal distentions was delivered, changes in electromyographic activity of the external oblique musculature (visceromotor response, VMR) and mean arterial pressure (pressor) responses were simultaneously measured. Vaginal distention produced VMR and pressor responses in all groups. These responses were significantly greater in ENDO than in the other groups, and greater in proestrus than metestrus. Although the overall amount of cystic tissue was greater in proestrous than metestrous rats, there was no correlation between these amounts and VMR or pressor responses. Acute spinalization (T8-T9) and bilateral pelvic, but not hypogastric, neurectomy attenuated both VMR and pressor responses, supporting the hypothesis that vaginal nociception involves suprathoracic spinal processing of information conveyed by the pelvic nerve. These effects on VMR and pressor responses to vaginal distention parallel behavioral escape responses to the same stimuli reported previously. The findings encourage continued use of VMR and pressor responses for further investigation of mechanisms underlying pain associated with ENDO and its potential treatment.
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Affiliation(s)
- Hiroshi Nagabukuro
- Program in Neuroscience, Florida State University, Tallahassee, FL 32306-1270, USA
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30
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Craft RM. Modulation of pain by estrogens. Pain 2007; 132 Suppl 1:S3-S12. [PMID: 17951003 DOI: 10.1016/j.pain.2007.09.028] [Citation(s) in RCA: 295] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2007] [Accepted: 09/28/2007] [Indexed: 11/28/2022]
Abstract
It has become increasingly apparent that women suffer a disproportionate amount of pain during their lifetime compared to men. Over the past 15 years, a growing number of studies have suggested a variety of causes for this sex difference, from cellular to psychosocial levels of analysis. From a biological perspective, sexual differentiation of pain appears to occur similarly to sexual differentiation of other phenomena: it results in large part from organizational and activational effects of gonadal steroid hormones. The focus of this review is the activational effects of a single group of ovarian hormones, the estrogens, on pain in humans and animals. The effects of estrogens (estradiol being the most commonly examined) on experimentally induced acute pain vs. clinical pain are summarized. For clinical pain, the review is limited to a few syndromes for which there is considerable evidence for estrogenic involvement: migraine, temporomandibular disorder (TMD) and arthritis. Because estrogens can modulate the function of the nervous, immune, skeletal, and cardiovascular systems, estrogenic modulation of pain is an exceedingly complex, multi-faceted phenomenon, with estrogens producing both pro- and antinociceptive effects that depend on the extent to which each of these systems of the body is involved in a particular type of pain. Forging a more complete understanding of the myriad ways that estrogens can ameliorate vs. facilitate pain will enable us to better prevent and treat pain in both women and men.
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Affiliation(s)
- Rebecca M Craft
- Department of Psychology, Washington State University, Pullman, WA 99164-4820, USA
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Yan T, Liu B, Du D, Eisenach JC, Tong C. Estrogen Amplifies Pain Responses to Uterine Cervical Distension in Rats by Altering Transient Receptor Potential-1 Function. Anesth Analg 2007; 104:1246-50, tables of contents. [PMID: 17456681 DOI: 10.1213/01.ane.0000263270.39480.a2] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Estrogen sensitizes responses to painful stimuli, but its contribution to acute and chronic pain from the uterine cervix is unknown. Previous studies link the excitatory transient receptor potiential-1 channel (TRPV-1) to sensitization in viscera, and show that estrogen increases TRPV-1 expression in afferents from the uterine cervix. Here, we tested whether estrogen enhanced responses to uterine cervical distension in rats, and whether this involved TRPV-1 channels. METHODS Ovariectomized rats, with or without estrogen replacement, were anesthetized and hypogastric nerve and abdominal muscle contraction reflex responses to graded uterine cervical distension were recorded. Single unit hypogastric nerve fiber firing was measured before and after acute treatment with the TRPV-1 antagonist, capsaizepine, or vehicle. RESULTS Abdominal muscle contraction reflex responses to uterine cervical distension were enhanced in estrogen-treated rats. Hypogastric afferent responses to cervical distension were reduced by capsaizepine in estrogen-treated animals, but were unaffected in ovariectomized animals without estrogen replacement. CONCLUSIONS These data suggest that the TRPV-1 channel is unimportant for normal mechanosensation in the cervix in the absence of estrogen, since capsaizepine failed to reduce responses to uterine cervical distension in rats without estrogen replacement. In contrast, TRPV-1 function is important for estrogen-induced sensitization. These data raise the possibility that acute and chronic pain coming from the cervix, such as labor or cancer, may be enhanced by estrogen and might be reduced by antagonists of TRPV-1.
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Affiliation(s)
- Tao Yan
- Department of Anesthesiology and the Center for the Study of Pharmacologic Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1009, USA
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32
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Ji Y, Tang B, Traub RJ. Modulatory effects of estrogen and progesterone on colorectal hyperalgesia in the rat. Pain 2006; 117:433-442. [PMID: 16154701 DOI: 10.1016/j.pain.2005.07.011] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2005] [Revised: 06/27/2005] [Accepted: 07/20/2005] [Indexed: 10/25/2022]
Abstract
The contribution of estrogen and progesterone to colorectal hyperalgesia was examined in female rats. The electromyogram recorded from the abdominal wall (visceromotor response, vmr) and the discharge of lumbosacral dorsal horn neurons to colorectal distention (CRD) were measured in intact female, ovariectomized (OVx) and estradiol replaced OVx (E2; 50mug, 48h) rats with and without colonic inflammation. Colorectal hyperalgesia was transient in intact rats, but persisted at least 4h in E2 and OVx rats. The magnitude of hyperalgesia in E2 rats was greater than OVx which was greater than intact rats. Dorsal horn neurons that responded to CRD with an Abrupt (on and off with stimulus) excitatory discharge showed similar sensitivity to estradiol as the vmr following colonic inflammation. In contrast, inflammation did not increase the magnitude of response of excitatory neurons with sustained afterdischarges in any of the treatment groups. Intact female rats have a comparable plasma estrogen concentration to E2 rats, suggesting the difference in responses may have been due to antinociceptive effects of progesterone. This was tested by administering E2+/- progesterone (1mg) and measuring the vmr. Progesterone reduced the facilitation of the vmr produced by E2 before and following colonic inflammation. The present study suggests that estrogen replacement enhances visceral signal processing following colonic inflammation. Furthermore, progesterone may counteract the effects of estrogen on colorectal sensitivity.
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Affiliation(s)
- Yaping Ji
- Department of Biomedical Sciences and Research Center for Neuroendocrine Influences on Pain, University of Maryland Dental School, 666 W. Baltimore St., Rm 5-A-22, Baltimore, MD 21201, USA
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Sanoja R, Cervero F. Estrogen-dependent abdominal hyperalgesia induced by ovariectomy in adult mice: A model of functional abdominal pain. Pain 2005; 118:243-53. [PMID: 16202534 DOI: 10.1016/j.pain.2005.08.021] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2005] [Revised: 08/02/2005] [Accepted: 08/18/2005] [Indexed: 12/16/2022]
Abstract
Some abdominal pain syndromes are characterized by persistent pain without demonstrable pathology. Many of them are prevalent in women and it is known that sex hormones are associated with differences in pain perception between males and females. To model a process of functional abdominal pain in females we studied the time course and estrogen dependency of a hyperalgesic state induced by ovariectomy in adult mice. Three groups of C57/BL6 mice were used: virgin mice, proven breeders (2 or 3 successful pregnancies) and retired breeders (more than three successful pregnancies). Within each group, a third of the mice were ovariectomized (OVX), a third received sham surgery and a third were controls. OVX mice, but not sham or controls, developed a robust mechanical hyperalgesia and allodynia in the abdomen, hindlimbs and proximal tail, but not in the forelimbs, that was established 4 weeks after OVX and lasted for the 7 weeks of the experiment. Increases in visceral sensitivity were also observed in OVX mice. Thermal pain thresholds (hot plate) remained unchanged. The reproductive history of the animals had no influence on the hyperalgesia. In another series of experiments a slow release pellet containing 17beta-estradiol was implanted in half of the OVX mice and a similar pellet without the hormone in the other half. Hormone replacement prevented the development of hyperalgesia in OVX animals but did not stop the involution of the internal reproductive organs. We conclude that OVX in mice provides a useful model for a hormonally dependent hyperalgesic state resembling functional pain.
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Affiliation(s)
- Raul Sanoja
- Anesthesia Research Unit Faculty of Medicine, Faculty of Dentistry and McGill Center for Pain Research, McGill University, Montréal, Quebec, Canada
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Terner JM, Lomas LM, Picker MJ. Influence of estrous cycle and gonadal hormone depletion on nociception and opioid antinociception in female rats of four strains. THE JOURNAL OF PAIN 2005; 6:372-83. [PMID: 15943959 DOI: 10.1016/j.jpain.2005.01.354] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 08/11/2004] [Revised: 01/10/2005] [Accepted: 01/18/2005] [Indexed: 11/15/2022]
Abstract
UNLABELLED Evidence suggests that gonadal hormones can modulate sensitivity to nociceptive stimuli and opioid antinociception. However, cross-study comparisons addressing the nature of this modulation have been complicated by a number of methodologic factors, including the use of different rodent strains and opioids. The present study examined the influence of estrous cycle and gonadal hormone depletion (ovariectomy) on thermal nociception and opioid antinociception in female F344, Lewis, Long Evans, and Wistar rats. Estrous cycle-dependent differences in nociceptive sensitivity were not observed in any of the strains. Ovariectomy decreased nociceptive sensitivity relative to their intact female counterparts. In normal cycling females, morphine and buprenorphine were generally most potent in metestrus and proestrus and least potent in estrus. The magnitude of these differences was consistently larger with buprenorphine. Ovariectomy increased the antinociceptive potency of morphine and buprenorphine, with this effect also being larger with buprenorphine. These data suggest that in adult females of a number of rat strains, estrous cycle and gonadal hormone depletion modulate the antinociceptive potency of opioids, with the magnitude of this effect being dependent on the type of opioid. In contrast, depletion of gonadal hormones, but not estrous cycle, modulates thermal nociceptive sensitivity in adult female rats. PERSPECTIVE Gonadal hormones influence opioid antinociception, and this effect is apparent across different genetic backgrounds. These results suggest that the phase of the menstrual cycle might alter the effectiveness of certain opioids administered to relieve pain in women.
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Affiliation(s)
- Jolan M Terner
- Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3270, USA.
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Ma B, Rong W, Dunn PM, Burnstock G. 17beta-estradiol attenuates alpha, beta-meATP-induced currents in rat dorsal root ganglion neurons. Life Sci 2005; 76:2547-58. [PMID: 15769479 DOI: 10.1016/j.lfs.2004.10.047] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2004] [Accepted: 10/15/2004] [Indexed: 10/25/2022]
Abstract
The effects of 17beta-estradiol on the alpha,beta-me ATP-induced currents were studied on dorsal root ganglion (DRG) neurons using whole-cell recording technique. Three types of currents (transient, sustained or biphasic) were evoked by alpha,beta-me ATP in acutely dissociated DRG neurons. When neurons were pre-incubated with 17beta-estradiol (10-1000 nM) for 4 min, an inhibition of the transient current and the transient component of the biphasic current was observed. In contrast, 17beta-estradiol did not have any significant effect on the sustained current evoked by alpha,beta-meATP. The inhibitory effects were concentration-dependent, reversible and could be blocked by the estradiol receptor inhibitor, ICI 182,780 (1 microM). However, bovine serum albumin-conjugated 17beta-estradiol (17beta-estradiol-BSA, 10 nM) failed to mimic the effects of 17beta-estradiol. 17alpha-estradiol, the inactive isoform, did not have significant effects on alphabeta-meATP-induced currents, either. Sustained currents induced by ATP (100 microM) in nodose ganglion (NG), superior cervical ganglion (SCG) and otic ganglion (OTG) neurons were not affected by 17beta-estradiol. These results suggest that the female gonadal hormone, 17beta-estradiol, might participate in control of pain by modulating P2X3 receptor-mediated events in sensory neurons.
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Affiliation(s)
- Bei Ma
- Department of Physiology, Second Military Medical University, 800, Xiangyin Road, Shanghai, 200433, China.
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Liu B, Eisenach JC, Tong C. Chronic Estrogen Sensitizes a Subset of Mechanosensitive Afferents Innervating the Uterine Cervix. J Neurophysiol 2005; 93:2167-73. [PMID: 15774714 DOI: 10.1152/jn.01012.2004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Estrogen increases reflex nocifensive responses to distension of the uterus and the urinary bladder, but estrogen's effects on afferent response to distension of the uterine cervix, the site of obstetric and some gynecologic pain, has not been studied. Here, single fiber recording of hypogastric nerve responses to uterine cervical distension were obtained from ovariectomized (OVX) rats and OVX rats treated with estrogen (ES). Spontaneous activity was greater in the ES group (13 of 24 units; 54%) than in the OVX group (6 of 27 units; 22%). ES differentially altered the response of low- and high-threshold units to distension. For high-threshold units, firing frequency was increased two- to fourfold with 60–100 gm distension in ES compared with OVX groups ( P < 0.05). In contrast, the response of low-threshold units to distension was not altered by ES. About one-half of units tested in each group responded to a temperature increase from 35 to 49°C. A greater proportion of thermosensitive units were also mechanosensitive in the ES group (7 of 8 afferents, 88%) than in the OVX group (5 of 11 afferents, 45%). Acute application of ES in OVX rats failed to evoke or increase distension-induced responses. These data show the polymodal nature of afferent fibers innervating the uterine cervix. Increased spontaneous activity with ES may play a part in remodeling of the cervical tissue, whereas selective sensitization of high-threshold units by ES might underlie increased pain responses to cervical distension. Failure of acute ES treatment to mimic this suggests a genomic effect.
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Affiliation(s)
- Baogang Liu
- Deptartment of Anesthesiology and Center for Study of Pharmacological Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
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Millecamps M, Etienne M, Jourdan D, Eschalier A, Ardid D. Decrease in non-selective, non-sustained attention induced by a chronic visceral inflammatory state as a new pain evaluation in rats. Pain 2004; 109:214-224. [PMID: 15157681 DOI: 10.1016/j.pain.2003.12.028] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2003] [Revised: 12/18/2003] [Accepted: 12/29/2003] [Indexed: 10/26/2022]
Abstract
The aim of this study was to develop a new behavioral pain test based on the evaluation of cognitive capacity impairments in rats with colitis and to determine the impact of different acute analgesic treatments. Colitis was induced in rats by an enema containing 2,4,6-trinitrobenzen sulfonic acid. Visual non-selective, non-sustained attentional level was assessed by a new behavioral testing procedure. Animals were familiarized on three consecutive days with an open field containing four small, similar, familiar objects. On the day of testing, one of the objects was randomly replaced by a new one. Attentional level was determined by the ability of the rat to perceive this small modification to its familiar environment. The effect of morphine, acetaminophen, aspirin or ibuprofen treatment was assessed on testing day and compared with that observed during a Von Frey test to assess referred tactile hypersensitivity of the skin of the lower back. Rats with colitis had decreased attentional level but no change in their locomotor activity, interest in the environment or memory encoding. Morphine (1 mg/kg, s.c. and 10 microg/rat, i.t.) and acetaminophen (200 mg/kg, p.o.) had a beneficial effect on attentional level and on referred tactile hypersensitivity. Testing for the latter showed that aspirin and ibuprofen (400 mg/kg, p.o.) were ineffective. The decrease in visual non-selective, non-sustained attention induced by chronic inflammatory painful state can be relieved by effective analgesic treatments. This finding could lead to the development of a new behavioral test to assess spontaneous pain in chronic painful subjects.
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Affiliation(s)
- Magali Millecamps
- INSERM/UdA E 9904, Laboratoire de Pharmacologie Médicale, Faculté de Médecine, 63001 Clermont-Ferrand Cedex 1, France
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Walf AA, Frye CA. Anti-nociception following exposure to trimethylthiazoline, peripheral or intra-amygdala estrogen and/or progesterone. Behav Brain Res 2003; 144:77-85. [PMID: 12946597 DOI: 10.1016/s0166-4328(03)00067-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Estradiol (E(2)) and/or progesterone (P) to the amygdala may influence stress-induced analgesia following predator odor, trimethylthiazoline (TMT), exposure. Ovariectomized (ovx) rats were administered subcutaneous (SC) or intra-amygdala vehicle, E(2), P, or E(2)+P. The effects on performance in a test of pain sensitivity, the tailflick task, was observed in animals that experienced an acute exposure to TMT or no odor (control) in a small chamber. Rats that were exposed to TMT had increased tailflick latencies compared to rats not exposed to TMT, this was partially attenuated by the opiate antagonist naloxone. Systemic E(2), P, or E(2)+P increased tailflick latencies compared to vehicle administration to ovx rats. Ovx rats administered E(2)+P to the amygdala had increased tailflick latencies compared to control rats. These data suggest that following exposure to predator odor, pain sensitivity in the tailflick task is decreased and that E(2) and/or P may have actions in the amygdala to produce similar anti-nociceptive effects.
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Affiliation(s)
- Alicia A Walf
- Department of Psychology, The University at Albany-SUNY, 1400 Washington Avenue, Albany, NY 12222, USA
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Abstract
A rat model of endometriosis, in which pieces of uterine horn (versus fat in controls) are autotransplanted into the abdomen where they form cysts, reduces fecundity and produces vaginal hyperalgesia. The cysts gradually enlarge over a 2-month period postsurgically and then plateau. Cysts regress with low estrogen levels and reappear when they rise. Based on the hypothesis that the vaginal hyperalgesia depends upon the cysts, this study tested two predictions: that (1) the hyperalgesia would develop postsurgically in parallel with the cysts, and (2) the hyperalgesia would vary with estrous, being greatest when estrogen levels are high (proestrus) and least when low (estrus). In rats trained to escape vaginal distention, percentage escape responses to different distention volumes were measured across the rat's 4-day estrous cycle for 2.5 months before and up to 4 months after autotransplantation of uterus (n=9) or fat (n=6) in abdominal sites. Vaginal pressures were also measured. In rats with uterine but not fat autotransplants, escape percentages increased postsurgically over a 2-month period and then plateaued. The increase was greatest in proestrus and failed to occur in estrus. Vaginal pressures were unchanged in all groups. These results strongly support the hypothesis that the vaginal hyperalgesia depends upon the cysts. Because the cysts were located in sites remote from the vagina, the hyperalgesia involves viscero-visceral interactions and is likely centrally mediated, whereas the estrous modulation could involve hormonal actions either on the cysts or, more likely, on vaginal afferent fibers, and/or on central neurons.
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Affiliation(s)
- Angie M Cason
- Program in Neuroscience, Florida State University, Tallahassee, FL 32306-1270, USA
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40
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Estrogen modulates the visceromotor reflex and responses of spinal dorsal horn neurons to colorectal stimulation in the rat. J Neurosci 2003. [PMID: 12736360 DOI: 10.1523/jneurosci.23-09-03908.2003] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Many gastrointestinal pain syndromes are more prevalent in women than men, suggesting a gonadal steroid influence. We characterized the effects of estrogen on two responses to colorectal distention (CRD) in the rat: the visceromotor reflex (vmr) and L6-S1 dorsal horn neuron activity (ABRUPT and SUSTAINED neurons). Ovariectomized rats were injected with estrogen, and responses to innocuous and noxious intensities of CRD were measured between 4 hr and 14 d after injection and compared with ovariectomized and intact, cycling rats. Plasma estrogen levels were determined at each time point. Ovariectomy significantly decreased the magnitude of the vmr and ABRUPT neuron response to CRD compared with cycling rats. Four and 48 hr after estrogen injection (10 microg), the magnitude of the vmr and ABRUPT neuron response returned to the level or greater than that of cycling rats. All responses were comparable with ovariectomized rats by 7 d. These results paralleled the plasma estrogen concentration. Fifty micrograms of estrogen did not further increase the magnitude of the vmr or neuronal response 48 hr after estrogen but did extend the period of the increased ABRUPT neuron response to 14 d. Estrogen did not affect the response of SUSTAINED neurons. In a separate experiment, the response to innocuous CRD was sensitized in estrogen-treated rats but not ovariectomized or cycling rats. The present data suggest that estrogen modulates the spinal cord processing and reflex responses to innocuous and noxious colorectal stimuli in female rats and may contribute to alterations in sensory processing associated with irritable bowel syndrome.
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Bennett HL, Gustafsson JA, Keast JR. Estrogen receptor expression in lumbosacral dorsal root ganglion cells innervating the female rat urinary bladder. Auton Neurosci 2003; 105:90-100. [PMID: 12798205 DOI: 10.1016/s1566-0702(03)00044-4] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
We have investigated whether bladder afferent neurons are likely to be targets for circulating estrogens by mapping estrogen receptor (ER) distribution in lumbosacral dorsal root ganglia (DRG) of adult female rats. Sensory neurons innervating either the detrusor or trigone regions were identified by application of fluorescent retrograde tracer dyes to the bladder wall. Labelled neurons were classified by their immunoreactivity for either type of ER (ERalpha or ERbeta) and further compared with subpopulations of neurons containing substance P, calcitonin gene-related peptide and vanilloid receptor (a marker of polymodal nociceptors). Both ER types were expressed in numerous sensory neurons of either upper lumbar (L1/L2) or lower lumbar/sacral (L6/S1) ganglia and there was almost complete coexpression of ERalpha and ERbeta. ER-positive neurons were mainly small-medium size (18-25-microm diameter), indicating that they may be nociceptors and/or supply visceral targets. Most bladder-projecting neurons expressed ERs and the majority of these also expressed neuropeptides or vanilloid receptor. Afferent neurons supplying detrusor and trigone regions had similar immunohistochemical features. About a third of the bladder-projecting neurons expressed both ER and vanilloid receptor, suggesting a mechanism by which estrogens could influence bladder pain. The prevalence of different chemical classes of ER-positive bladder-projecting neurons was reflected throughout the entire population of neurons in dorsal root ganglia of these spinal levels, suggesting that neurons supplying other pelvic visceral targets may have similar chemical profiles. These results suggest that many functional classes of sensory neurons innervating the lower urinary tract are likely to be targets for circulating estrogens, including many nociceptor neurons. The coexistence of ERalpha and ERbeta suggests a broad range of potential mechanisms by which estrogens may exert their genomic effects in this system.
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Affiliation(s)
- Haley L Bennett
- Prince of Wales Medical Research Institute, University of New South Wales, NSW 2052, Sydney, Australia
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42
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Clark AS, Guarraci FA, Megroz AB, Porter DM, Henderson LP. The display of sexual behaviors by female rats administered ICI 182,780. Horm Behav 2003; 43:454-64. [PMID: 12788291 DOI: 10.1016/s0018-506x(03)00029-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
ICI 182,780 (ICI) is a pure antiestrogen that when administered systemically does not cross the blood-brain barrier, thus its actions are limited to the periphery. Four experiments were conducted to test the effects of ICI on the display of sexual behaviors in ovariectomized rats. Experiment 1 examined the effects of three doses of ICI (250, 500, and 750 micro g/rat) on sexual receptivity and paced mating behavior in rats primed with estradiol benzoate (EB) in combination with progesterone (P). Experiments 2 and 3 compared the display of sexual behaviors in rats primed with EB+P or EB alone and administered either 250 micro g ICI (Experiment 2) or 500 micro g ICI (Experiment 3). Experiment 4 tested the effects of ICI (250 and 500 micro g) on the expression of estrogen-induced progestin receptors in the uterus. ICI did not affect the display of sexual receptivity in any experiment. In rats primed with EB+P, paced mating behavior was altered by the 500 and 750 micro g, but not the 250 micro g, doses of ICI. The lowest (250 micro g) dose of ICI did alter paced mating behavior in rats primed with EB alone. The effects of ICI on paced mating behavior were manifested by a substantial lengthening of contact-return latencies following intromissions and ejaculations. The percentage of exits were not affected by ICI. Estrogen stimulation of uterine weight and induction of uterine progestin receptors was suppressed by ICI (250 and 500 micro g). ICI effects on paced mating behavior in hormone-primed female rats are likely to reflect antiestrogenic actions in the periphery, including interference with the estrogen induction of progestin receptors.
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Affiliation(s)
- Ann S Clark
- Department of Psychological and Brain Sciences, 6207 Moore Hall, Dartmouth College, Hanover, NH 03755, USA.
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Mitrovic I, Margeta-Mitrovic M, Bader S, Stoffel M, Jan LY, Basbaum AI. Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences. Proc Natl Acad Sci U S A 2003; 100:271-6. [PMID: 12496346 PMCID: PMC140949 DOI: 10.1073/pnas.0136822100] [Citation(s) in RCA: 157] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The analgesia produced by inhibitory G protein-coupled receptor agonists involves coordinated postsynaptic inhibition via G protein-coupled inwardly rectifying potassium channels (GIRKs) and presynaptic inhibition of neurotransmitter release through regulation of voltage-gated Ca(2+) channels. Here, we used mice lacking the GIRK2 channel subunit to assess the relative contribution of these two effector systems to nociceptive processing in male and female mice. Compared with female WT mice, male WT mice exhibited higher pain thresholds and enhanced opioid (morphine) and alpha(2)-adrenergic (clonidine) receptor-induced antinociception in a spinal reflex test. The GIRK2-null mutation reduced the "pain" threshold in male but not in female mice, effectively eliminating the sex differences in pain threshold. In addition, deletion of GIRK2 channels in mutant mice largely eliminated clonidine antinociception and significantly decreased morphine antinociception. Furthermore, the more pronounced morphine and clonidine-induced antinociception in male mice disappeared in the GIRK2 mutants. Based on the almost complete loss of clonidine-induced antinociception in the mutant mice, we conclude that it is primarily mediated by postsynaptic alpha(2)-adrenergic receptors. In contrast, the significant residual morphine effect in the mutant mice points to the presynaptic mu opioid receptor as a major contributor to its analgesic action. Finally, our results suggest that the reduced pain responsiveness of male compared with female mice results in part from GIRK2-coupled postsynaptic receptors that are activated by endogenous antinociceptive systems.
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Affiliation(s)
- Igor Mitrovic
- Department of Physiology, University of California, San Francisco, 94143, USA
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Papka RE, Mowa CN. Estrogen Receptors in the Spinal Cord, Sensory Ganglia, and Pelvic Autonomic Ganglia. INTERNATIONAL REVIEW OF CYTOLOGY 2003; 231:91-127. [PMID: 14713004 DOI: 10.1016/s0074-7696(03)31003-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Until relatively recently, most studies of the effects of estradiol in the nervous system focused on hypothalamic, limbic, and other brain centers involved in reproductive hormone output, feedback, and behaviors. Almost no studies addressed estradiol effects at the spinal cord or peripheral nervous system level. Prior to the mid-1960s-1970s, few studies examined neural components of reproductive endocrine organs (e.g., ovary or testis) or the genital organs (e.g., uterus or penis) because available data supported endocrine regulation of these structures. Over the last two decades interest in and studies on the innervation of the genital organs have burgeoned. Because of the responsiveness of genital organs to sex steroid hormones, these neural studies seeded interest in whether or not autonomic and sensory neurons that innervate these organs, along with their attendant spinal cord circuits, also are responsive to sex hormones. From the mid-1980s there has been a steady growth of interest in, and studies of the neuroanatomy, neurochemistry, neural connectivity, and neural functional aspects in reproductive organs and the response of these parameters to sex steroids. Thus, with the growth of probes and techniques, has come studies of anatomy, neurochemistry, and circuitry of sex hormone-responsive neurons and circuits in the spinal cord and peripheral nervous system. This review focuses on estrogen receptors in sensory, autonomic, and spinal cord neurons in locales that are associated with innervation of female reproductive organs.
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Affiliation(s)
- R E Papka
- Department of Neurobiology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272, USA
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Abstract
In the United States and other Western cultures, a greater number of women seek health care services for symptoms of functional pain disorders, including irritable bowel syndrome, than men. Recent clinical trials indicate that gender differences in responsiveness to drug therapy also occur. Several lines of inquiry have focused on explaining this gender-related difference due to the higher prevalence of these disorders in women. Evidence of a physiologic component is based on gender differences in gastrointestinal transit time, visceral sensitivity, central nervous system pain processing, and specific effects of estrogen and progesterone on gut function. Additional factors may play a role, including gender-related differences in neuroendocrine, autonomic nervous system, and stress reactivity, which are related to bowel function and pain. However, the link between these measures and gut motility or sensitivity remains to be clarified. Psychological characteristics, including somatization, depression, and anxiety as well as a history of sexual abuse, may also contribute to gender-related differences in the prevalence of irritable bowel syndrome. Although gender differences in the therapeutic benefit of serotonergic agents have been observed, less is known about potential differences in responsiveness to nondrug therapies for irritable bowel syndrome.
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Affiliation(s)
- Lin Chang
- UCLA/CURE Neuroenteric Disease Program, Department of Medicine, and Brain Research Institute, UCLA School of Medicine, Los Angeles, California 90073, USA.
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46
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47
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Bradshaw HB, Berkley KJ. Estrogen replacement reverses ovariectomy-induced vaginal hyperalgesia in the rat. Maturitas 2002; 41:157-65. [PMID: 11836047 DOI: 10.1016/s0378-5122(01)00261-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
OBJECTIVES The loss of ovarian function in women through aging or oophorectomy is often associated with the development of vaginal hyperalgesia that can be alleviated with estrogen replacement. This study examined if ovariectomy in rats would similarly give rise to vaginal hyperalgesia, and, if so, whether estrogen replacement would alleviate it. METHODS Female rats were trained to perform an operant response to escape vaginal distention delivered by inflating a balloon located in mid-vaginal canal. Percent escape responses to eight different volumes of distention measured in normally cycling rats were compared with measures made in the same rats following ovariectomy (OVX) or sham ovariectomy (shamOVX), and then, in the OVX group, estrogen replacement (OVX+E2). Pressures exerted by the eight volumes on the vaginal wall were also measured, thereby permitting assessment of vaginal tone. RESULTS Whereas overall escape response percentages after OVX, but not shamOVX, were significantly higher to the largest six distention volumes compared with responses during cycling, there were individual differences in the amount of hyperalgesia. Following OVX+E2, escape response percentages decreased in all but one rat. Vaginal tone after OVX, shamOVX or OVX+E2 did not differ from overall vaginal tone in cycling rats. CONCLUSIONS Ovariectomy in rats evokes a variable amount of vaginal hyperalgesia that can be alleviated by estrogen replacement in most cases. Thus, the ovariectomized rat appears to provide a useful model for the study of mechanisms underlying the dyspareunia that is associated with loss of ovarian function in women.
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Affiliation(s)
- Heather B Bradshaw
- Program in Neuroscience, Department of Psychology, Florida State University, Copeland Street, Tallahassee, FL 32306-1270, USA
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48
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Gintzler AR, Liu NJ. The maternal spinal cord: biochemical and physiological correlates of steroid-activated antinociceptive processes. PROGRESS IN BRAIN RESEARCH 2001; 133:83-97. [PMID: 11589147 DOI: 10.1016/s0079-6123(01)33007-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Physiological gestation, as well as the simulation of the associated changes in estrogen and progesterone, is associated with significant elevations in nociceptive response thresholds. This is mediated by spinal cord kappa- and delta-opIoid systems. The predominant spinal mu-opioid system does not appear to participate. One hallmark of pregnancy- and hormonally-induced antinociception is the multiplicative interaction among its components. Approximately 40% results from spinal kappa/delta analgesic synergy on which is superimposed an additional increment (approximately 60%) of synergy that results from the interaction between descending spinal alpha 2-noradrenergic and spinal kappa/delta activities. An intact hypogastric nerve is required for the spinal alpha 2-noradrenergic component. This would explain the requirement for an intact hypogastric nerve in order for the antinociception of pregnancy and its hormonal simulation to be fully manifest. The predominant means by which spinal dynorphin-containing neurons adjust to increased demand is increased post-translational processing of dynorphin precursor intermediates which are present at approximately 10x the concentration of mature dynorphin peptides (1-17 and 1-8). This is indicated by the concomitant decline (approximately 50%) in the spinal cord content of dynorphin precursors and increase (approximately 87%) in the content of prohormone convertase 2, a processing enzyme sufficient to generate mature dynorphin peptides from prodynorphin. The presence of 'high gain' multiplicative spinal opioid antinociceptive pathways that can be activated by estrogen and progesterone has hyperalgesic implications as well, i.e. it could result in disproportionately increased pain responsiveness. This might explain, in part, findings that women are more prone to recurrent pain and pain of greater duration and intensity than men. The underlying mechanisms of gestational antinociception could point the way to pain pharmacotherapies that are gender-based.
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Affiliation(s)
- A R Gintzler
- Department of Biochemistry, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
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Berkley KJ, Cason A, Jacobs H, Bradshaw H, Wood E. Vaginal hyperalgesia in a rat model of endometriosis. Neurosci Lett 2001; 306:185-8. [PMID: 11406326 DOI: 10.1016/s0304-3940(01)01906-1] [Citation(s) in RCA: 67] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
This study examined whether a rat model of surgically-induced endometriosis that reduces fertility also evokes vaginal hyperalgesia along with changes in vaginal compliance. In nine rats trained to escape vaginal distention, percent escape responses to different volumes of vaginal distention were measured for 2.5 months before and after endometriosis or sham surgery. Vaginal pressures were also measured simultaneously to provide an estimate of vaginal compliance. Endometriosis (or sham) was induced by autotransplantation of small pieces of uterus (or fat) on mesenteric cascade arteries, abdomen, and ovary. Escape responses were significantly increased only in rats whose autotransplants had formed cysts. Vaginal pressures, however, remained unchanged. This vaginal hyperalgesia may involve a process of viscero-visceral referred hyperalgesia.
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Affiliation(s)
- K J Berkley
- Program in Neuroscience, Copeland Street, Department of Psychology, Florida State University, Tallahassee, FL 32306-1270, USA.
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Abstract
Multi- and single-unit recording was performed in the gracile nucleus in urethane-anesthetized rats to examine estrous variations in responses of its neurons to brushing the hindquarters and mechanical stimulation of the uterus, vaginal canal, cervix, and colon. Six rats each were studied in each of the four estrous stages: proestrus (P), estrus (E), metestrus (M), and diestrus (D). The magnitude of multi-unit responses to gentle brushing of the perineum, hip, and tail, but not the foot and leg, was significantly greater during proestrus than during other stages. Of 70 single units responsive to brush, 56 (80%) responded to stimulation of at least one viscus. Although this percentage did not change with estrous stage, the direction and latency of some responses did. Pressure on the cervix evoked significantly more inhibitory (vs excitatory) responses in P than in E and M, and the response latency was significantly longer in D and P than in E and M. The direction of response to vaginal distention did not change with estrous stage, but response latency was significantly longer in D than in P and E. Uterine distention evoked significantly more inhibitory responses in D than in P, with no estrous changes in latency. Responses to colon distention did not change. These variations in both magnitude of response to tactile stimulation and characteristics of response to stimulation of reproductive organs, but not the colon, correlate with changes in mating behaviors of the female rat, suggesting that the gracile nucleus is a component of neural systems that control reproductive behaviors.
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