|
1
|
Katz P. 'I am in pain': neuroethics, philosophy of language, and the representation of pain. THEORETICAL MEDICINE AND BIOETHICS 2025; 46:13-30. [PMID: 40009317 DOI: 10.1007/s11017-025-09700-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/12/2025] [Indexed: 02/27/2025]
Abstract
This essay considers the idea of 'representation' and pain in neuroscience, continental philosophy, and analytic philosophy. To do so, it considers two forms of representation: linguistic representation refers to how words stand in for experiences or things, while mental representation involves the mind's internal depiction of external reality. First, I consider how the question of pain may be conveyed as a question of representation through the McGill Pain Quotient. I then turn to phenomenology to consider how pain cuts straight through representation. Pain is simultaneously an extra-mental experience and an introspective phenomenal experience involving the affect of pain and the social expression of that affect. But to illustrate how pain lacks intention, I consider how the term 'representation' in the neuroscience on cognitive empathy for pain obfuscates the affective ontology of pain experiences. Linguistic expression of pain may suggest belief and representational data, while the phenomenological experience centers around the affective and embodied. Ultimately, the response to pain plays out in social acknowledgement, and both linguistic and mental representation offer necessary but insufficient understandings of ethical acknowledgement. To that end, neuroethics can offer naturalist, physicalist grounds to affirm both the analytic and continental theses about pain and language.
Collapse
Affiliation(s)
- Peter Katz
- California Northstate University, Elk Grove, USA.
| |
Collapse
|
|
2
|
Quaghebeur J, Wyndaele JJ, Petros P. A Critical Examination of Ligamentous Pathogenesis of Bladder Pain/Lower Urinary Tract Symptoms Using the UEDA Criteria. Int Neurourol J 2024; 28:96-105. [PMID: 38956769 PMCID: PMC11222830 DOI: 10.5213/inj.2346344.172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 04/07/2024] [Indexed: 07/04/2024] Open
Abstract
To critically analyse the relationship of bladder pain syndrome (BPS/IC), as defined, to the posterior fornix syndrome, "PFS" predictably co-occurring bladder urgency, frequency, nocturia, chronic pelvic pain, emptying symptoms/retention, caused by uterosacral ligament (USL) laxity and cured by USL repair. The starting and end points of this paper are the questions, "Are there arguments that BPS/IC can, in some cases, be linked to PFS?" And if so, "To what extent?" We used the criteria required by Ueda for proper diagnosis: "understanding symptoms, detecting abnormal findings and verifying them as a cause of the symptoms." Literature, diagnostic and surgical, indicate that chronic pelvic pain "of unknown origin" can be caused by unsupported visceral pelvic plexuses because of weak USLs; these cause fire of afferent impulses, which the brain mistakenly interprets as coming from the end-organ itself (i.e., genitourinary pain, lower urinary tract symptoms). The same lax USLs can also weaken the pelvic muscles which contract to stretch the vagina to support the urothelial stretch receptors from below: these may prematurely fire off afferent impulses to activate micturition at lower bladder volumes, interpreted as urgency. A speculum placed in the vagina can relieve pain and urgency by mechanically supporting the vaginal wall and USLs, thus predicting an eventual cure by USL repair. There is need to evaluate what percentage of women with known BPS/IC also pass the criteria for PFS. Identifying a significant percentage of BPS/IC women with the causative relation between PFS pathogenesis and BPS/ IC may open a new way of diagnosing and treating BPS/IC in some women.
Collapse
Affiliation(s)
- Jörgen Quaghebeur
- Faculty of Medicine and Health Sciences, University of Antwerp, Edegem, Belgium
- Department of Urology, University of Antwerp, Edegem, Belgium
| | | | - Peter Petros
- University of Western Australia School of Engineering and Mathematical Sciences, Elizabeth Bay, NSW, Australia
| |
Collapse
|
|
3
|
Janko D, Thoenes K, Park D, Willoughby WR, Horton M, Bolding M. Somatotopic Mapping of the Fingers in the Somatosensory Cortex Using Functional Magnetic Resonance Imaging: A Review of Literature. Front Neuroanat 2022; 16:866848. [PMID: 35847829 PMCID: PMC9277538 DOI: 10.3389/fnana.2022.866848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 05/16/2022] [Indexed: 11/29/2022] Open
Abstract
Multiple studies have demonstrated finger somatotopy in humans and other primates using a variety of brain mapping techniques including functional magnetic resonance imaging (fMRI). Here, we review the literature to better understand the reliability of fMRI for mapping the somatosensory cortex. We have chosen to focus on the hand and fingers as these areas have the largest representation and have been the subject of the largest number of somatotopic mapping experiments. Regardless of the methods used, individual finger somatosensory maps were found to be organized across Brodmann areas (BAs) 3b, 1, and 2 in lateral-to-medial and inferior-to-superior fashion moving from the thumb to the pinky. However, some consistent discrepancies are found that depend principally on the method used to stimulate the hand and fingers. Therefore, we suggest that a comparative analysis of different types of stimulation be performed to address the differences described in this review.
Collapse
Affiliation(s)
- Daniel Janko
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Kristina Thoenes
- Edward Via College of Osteopathic Medicine Auburn, Auburn, AL, United States
| | - Dahye Park
- School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - W. R. Willoughby
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Meredith Horton
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Mark Bolding
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, United States
| |
Collapse
|
|
4
|
Ball T, Aljuboori Z, Nauta H. Punctate Midline Myelotomy: A Historical Overview and Case Series with Detailed Efficacy and Side Effect Profiles. World Neurosurg 2021; 154:e264-e276. [PMID: 34256176 DOI: 10.1016/j.wneu.2021.07.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To review our experience with punctate midline myelotomy (PMM) for malignant and benign visceral pain with an emphasis on detailed side-effect profiles and efficacy. METHODS Thirteen adults (5 men) underwent microsurgical transverse-crush PMM. RESULTS Median follow-up for the benign pain group (n = 6) was 17.5 months (10-72) and for the malignant group (n = 7) was 8 months (0.5-31). Five of seven patients in the malignant pain group obtained excellent, lasting relief. Two had initial relief followed by worsening pain with disease progression. In the benign pain group, two patients with endodermal-origin pain (gastrointestinal tract, bladder) had complete, long-lasting relief. Three patients with mesodermal-origin pain (ureter) had excellent relief for 2-3 months, followed by recurrence in two and partial (40%) recurrence in the third. One man with pre-existing cervical myelopathy underwent PMM for benign testicular-region pain from which he had long-term relief but only transient relief of coexisting low-back and leg pain. There were no motor deficits in either group, and all patients remained ambulatory and continent. The most common side effect was transient numbness of the medial leg and foot. Two patients (both with pre-existing spinal pathology) reported persistent moderate reduction of bowel, bladder, and sexual sensation. CONCLUSIONS PMM offers substantial pain relief for carefully selected patients with intractable visceral pain. Relief from primarily endoderm-derived structures was most complete and long-lasting. Relief from mesoderm-derived structures was typically transient or incomplete. There was essentially no relief from pain of ectoderm-derived structures. Detailed preoperative counseling is important, especially for those with pre-existing neurologic deficits.
Collapse
Affiliation(s)
- Tyler Ball
- Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, USA.
| | - Zaid Aljuboori
- Department of Neurological Surgery, University of Washington, Seattle, Washington, USA
| | - Haring Nauta
- Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, USA
| |
Collapse
|
|
5
|
Chen H, Hu B, Lv X, Zhu S, Zhen G, Wan M, Jain A, Gao B, Chai Y, Yang M, Wang X, Deng R, Wang L, Cao Y, Ni S, Liu S, Yuan W, Chen H, Dong X, Guan Y, Yang H, Cao X. Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. Nat Commun 2019; 10:181. [PMID: 30643142 PMCID: PMC6331599 DOI: 10.1038/s41467-018-08097-7] [Citation(s) in RCA: 191] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 12/14/2018] [Indexed: 12/15/2022] Open
Abstract
Whether sensory nerve can sense bone density or metabolic activity to control bone homeostasis is unknown. Here we found prostaglandin E2 (PGE2) secreted by osteoblastic cells activates PGE2 receptor 4 (EP4) in sensory nerves to regulate bone formation by inhibiting sympathetic activity through the central nervous system. PGE2 secreted by osteoblasts increases when bone density decreases as demonstrated in osteoporotic animal models. Ablation of sensory nerves erodes the skeletal integrity. Specifically, knockout of the EP4 gene in the sensory nerves or cyclooxygenase-2 (COX2) in the osteoblastic cells significantly reduces bone volume in adult mice. Sympathetic tone is increased in sensory denervation models, and propranolol, a β2-adrenergic antagonist, rescues bone loss. Furthermore, injection of SW033291, a small molecule to increase PGE2 level locally, significantly boostes bone formation, whereas the effect is obstructed in EP4 knockout mice. Thus, we show that PGE2 mediates sensory nerve to control bone homeostasis and promote regeneration.
Collapse
Affiliation(s)
- Hao Chen
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
- Department of Orthopaedic Surgery, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215000, P. R. China
| | - Bo Hu
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
- Section of Spine Surgery, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, 200433, P. R. China
| | - Xiao Lv
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Shouan Zhu
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Gehua Zhen
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Mei Wan
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Amit Jain
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Bo Gao
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Yu Chai
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Mi Yang
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Xiao Wang
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Ruoxian Deng
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Lei Wang
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Yong Cao
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Shuangfei Ni
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Shen Liu
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Wen Yuan
- Section of Spine Surgery, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, 200433, P. R. China
| | - Huajiang Chen
- Section of Spine Surgery, Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, 200433, P. R. China
| | - Xinzhong Dong
- Howard Hughes Medical Institute and The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Yun Guan
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Huilin Yang
- Department of Orthopaedic Surgery, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215000, P. R. China.
| | - Xu Cao
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA.
| |
Collapse
|
|
6
|
Todorov P, Peneva P, Pechlivanova D, Georgieva S, Dzhambazova E. Synthesis, characterization and nociceptive screening of new VV-hemorphin-5 analogues. Bioorg Med Chem Lett 2018; 28:3073-3079. [PMID: 30078474 DOI: 10.1016/j.bmcl.2018.07.040] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 07/25/2018] [Accepted: 07/29/2018] [Indexed: 12/19/2022]
Abstract
In the present study, some new analogues of VV-hemorphin-5, modified at position 1 and 7 by the non-proteinogenic and/or natural amino acids followed the structures Xxx-Val-Val-Tyr-Pro-Trp-Thr-Gln-NH2 and Val-Val-Tyr-Pro-Trp-Thr-Yyy-NH2, where Xxx is Ile or Aib and Yyy is Lys/Orn/Dap/Dab were synthesized to investigate their potential antinociceptive activities. We report also the redox potentials and the acid/base properties as pKa values of these peptide analogues which were compared toward electrochemical behaviour of tryptophan containing peptides. All analogues showed a short lasting initial antinociceptive effect, however H2 hemorphin analogue is characterized with prolong and strong antinociceptive effect, while the other peptide analogues exerted more variable effects on the visceral nociception depending on the dose or time after the intracerebral injection.
Collapse
Affiliation(s)
- Petar Todorov
- Department of Organic Chemistry, University of Chemical Technology and Metallurgy, 1756 Sofia, Bulgaria.
| | - Petia Peneva
- Department of Organic Chemistry, University of Chemical Technology and Metallurgy, 1756 Sofia, Bulgaria
| | | | - Stela Georgieva
- Department of Analytical Chemistry, University of Chemical Technology and Metallurgy, 1756 Sofia, Bulgaria
| | - Elena Dzhambazova
- Department of Chemistry, Biochemistry, Physiology and Pathophysiology, Faculty of Medicine, Sofia University "St. Kliment Ohridski", 1407 Sofia, Bulgaria
| |
Collapse
|
|
7
|
Microstructural mechanisms of analgesia in percutaneous cervical cordotomy revealed by diffusion tensor imaging. J Clin Neurosci 2017; 45:311-314. [PMID: 28887076 DOI: 10.1016/j.jocn.2017.08.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 08/10/2017] [Indexed: 11/23/2022]
Abstract
The purpose of this study is to demonstrate the potential of diffusion tensor imaging (DTI) to reveal structural mechanisms underlying spinal ablative procedures, including percutaneous radiofrequency cordotomy (PRFC). PRFC is a surgical procedure that produces analgesia through focal ablation of the lateral spinothalamic tract (STT), thereby interrupting the flow of pain information from the periphery to the brain. To date, studies regarding mechanisms of analgesia after PRFC have been limited to postmortem cadaveric dissection and histology. However, with recent advances in DTI, the opportunity has arisen to study the STT non-invasively in vivo. In this technical note, an individual with successful pain relief following unilateral STT PRFC was examined using DTI, with the contralateral STT serving as an internal control. PRFC substantially reduced rostrocaudal directional DTI signal in the STT from the lesion in the cervical spinal cord through the pons and mesencephalon. Our findings confirm that focal ablation and anterograde degeneration accompany the analgesic effects of PRFC. In vivo imaging of the STT with DTI may contribute to surgical targeting for PRFC procedures, better understanding of the therapeutic and untoward effects of PRFC, and a deeper understanding of spinothalamic contributions to nociception.
Collapse
|
|
8
|
Konrad P. Dorsal root entry zone lesion, midline myelotomy and anterolateral cordotomy. Neurosurg Clin N Am 2015; 25:699-722. [PMID: 25240658 DOI: 10.1016/j.nec.2014.07.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
This review encompasses the most common spinal cord lesioning procedures used for the treatment of pain: dorsal root entry zone lesioning, open cordotomy, percutaneous cordotomy, and midline myelotomy. A literature review and summary of each technique regarding relevant anatomy, patient selection, surgical technique, outcomes, and complications are discussed. A general review of somatic and visceral pain pathways of the spinal cord is included, as each procedure requires an understanding of the advantages and disadvantages of various approaches to lesioning the spinal cord for pain. Neurosurgical education of these rarely used procedures needs to be included in residency and fellowship training.
Collapse
Affiliation(s)
- Peter Konrad
- Functional Neurosurgery, Neurological Surgery and Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
| |
Collapse
|
|
9
|
Lake WB, Konrad PE. Cordotomy procedures for cancer pain: A discussion of surgical procedures and a review of the literature. World J Surg Proced 2015; 5:111-118. [DOI: 10.5412/wjsp.v5.i1.111] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 01/02/2015] [Accepted: 02/02/2015] [Indexed: 02/06/2023] Open
Abstract
Treating pain in patients with terminal cancer is challenging but essential part of their care. Most patients can be managed with pharmacological options but for some these pain control methods are inadequate. Ablative spinal procedures offer an alternative method of pain control for cancer patients with a terminal diagnosis that are failing to have their pain controlled sufficiently by other methods. This paper provides a review of ablative spinal procedures for control of cancer pain. Patient selection, surgical methods, outcomes and complications are discussed in detail for cordotomy, dorsal root entry zone (DREZ) lesioning and midline myelotomy. Cordotomy is primarily done by a percutaneous method and it is best suited for patients with unilateral somatic limb and trunk pain such as due to sarcoma. Possible complications include unilateral weakness possibly respiratory abnormalities. Approximately 90% of patients have significant immediate pain relief following percutaneous cordotomy but increasing portions of patients have pain recurrence as the follow-up period increases beyond one year. The DREZ lesion procedure is best suited to patients with plexus invasion due to malignancy and pain confined to one limb. Possible complications of DREZ procedures include hemiparesis and decreased proprioception. Midline myelotomy is best suited for bilateral abdominal, pelvic or lower extremity pain. Division of the commissure is necessary to address bilateral lower extremity pain. This procedure is relatively rare but published case series demonstrate satisfactory pain control for over half of the patients undergoing the procedure. Possible complications include bilateral lower extremity weakness and diminished proprioception below the lesion level. Unlike cordotomy and DREZ this procedure offers visceral pain control as opposed to only somatic pain control. Ablative spinal procedures offer pain control for terminal cancer patients that are not able to managed medically. This paper provides an in depth review of these procedures with the hope of improving education regarding these underutilized procedures.
Collapse
|
|
10
|
Acupuncture for visceral pain: neural substrates and potential mechanisms. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:609594. [PMID: 25614752 PMCID: PMC4295157 DOI: 10.1155/2014/609594] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 12/13/2014] [Accepted: 12/13/2014] [Indexed: 12/17/2022]
Abstract
Visceral pain is the most common form of pain caused by varied diseases and a major reason for patients to seek medical consultation. Despite much advances, the pathophysiological mechanism is still poorly understood comparing with its somatic counterpart and, as a result, the therapeutic efficacy is usually unsatisfactory. Acupuncture has long been used for the management of numerous disorders in particular pain and visceral pain, characterized by the high therapeutic benefits and low adverse effects. Previous findings suggest that acupuncture depresses pain via activation of a number of neurotransmitters or modulators including opioid peptides, serotonin, norepinephrine, and adenosine centrally and peripherally. It endows us, by advancing the understanding of the role of ion channels and gut microbiota in pain process, with novel perspectives to probe the mechanisms underlying acupuncture analgesia. In this review, after describing the visceral innervation and the relevant afferent pathways, in particular the ion channels in visceral nociception, we propose three principal mechanisms responsible for acupuncture induced benefits on visceral pain. Finally, potential topics are highlighted regarding the future studies in this field.
Collapse
|
|
11
|
Anatomo-Functional Correlation between Head Zones and Acupuncture Channels and Points: A Comparative Analysis from the Perspective of Neural Therapy. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:836392. [PMID: 25506384 PMCID: PMC4260442 DOI: 10.1155/2014/836392] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 09/24/2014] [Accepted: 09/26/2014] [Indexed: 01/11/2023]
Abstract
Background. Neural therapy and traditional Chinese medicine (TCM) are part of complementary and alternative medicine in western world. Both of them share characteristics in diagnosis and therapeutics in search of changes in tenderness, pain, and skin stiffness related to visceral disease, as well as therapeutic procedures with specific stimuli on the skin that generate local, segmental, or remote reactions. Head zones explain segmental viscerocutaneous relations in neural therapy; however, interference fields and remote reactions after infiltration of local anesthetic go beyond this segmental distribution. Methods. This descriptive research required review and analysis of texts of Henry Head and traditional Chinese medicine. Results. Anatomical and functional relationships were found between Head zones in body, and head and neck with 14 acupuncture channels and their points. Anatomical areas of strong correlations were found: Head zones of heart and lung with heart and pericardium channels; Head zones of genitals with bladder and kidney channels. Strong functional relations between all Head zones, channels, and acupoints were found when following the pattern of segmental dermatomes; 235 acupuncture points were found in concordance.
Collapse
|
|
12
|
Yang FC, Tan T, Huang T, Christianson J, Samad OA, Liu Y, Roberson D, Davis BM, Ma Q. Genetic control of the segregation of pain-related sensory neurons innervating the cutaneous versus deep tissues. Cell Rep 2013; 5:1353-64. [PMID: 24316076 DOI: 10.1016/j.celrep.2013.11.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2012] [Revised: 09/28/2013] [Accepted: 11/04/2013] [Indexed: 12/30/2022] Open
Abstract
Mammalian pain-related sensory neurons are derived from TrkA lineage neurons located in the dorsal root ganglion. These neurons project to peripheral targets throughout the body, which can be divided into superficial and deep tissues. Here, we find that the transcription factor Runx1 is required for the development of many epidermis-projecting TrkA lineage neurons. Accordingly, knockout of Runx1 leads to the selective loss of sensory innervation to the epidermis, whereas deep tissue innervation and two types of deep tissue pain are unaffected. Within these cutaneous neurons, Runx1 suppresses a large molecular program normally associated with sensory neurons that innervate deep tissues, such as muscle and visceral organs. Ectopic expression of Runx1 in these deep sensory neurons causes a loss of this molecular program and marked deficits in deep tissue pain. Thus, this study provides insight into a genetic program controlling the segregation of cutaneous versus deep tissue pain pathways.
Collapse
Affiliation(s)
- Fu-Chia Yang
- Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA
| | - Taralyn Tan
- Department of Neurobiology, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA
| | - Tianwen Huang
- Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA
| | - Julie Christianson
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA
| | - Omar A Samad
- Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA
| | - Yang Liu
- Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA
| | - David Roberson
- Department of Neurobiology, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA
| | - Brian M Davis
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA
| | - Qiufu Ma
- Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA.
| |
Collapse
|
|
13
|
Kang Y, Zhao Y, Guo R, Zhang M, Wang Y, Mu Y, Wu A, Yue Y, Wu J, Wang Y. Activation of ERK signaling in rostral ventromedial medulla is dependent on afferent input from dorsal column pathway and contributes to acetic acid-induced visceral nociception. Neurochem Int 2013; 63:389-96. [DOI: 10.1016/j.neuint.2013.07.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Revised: 06/26/2013] [Accepted: 07/13/2013] [Indexed: 12/30/2022]
|
|
14
|
Hochman S, Gozal EA, Hayes HB, Anderson JT, DeWeerth SP, Chang YH. Enabling techniques for in vitro studies on mammalian spinal locomotor mechanisms. Front Biosci (Landmark Ed) 2012; 17:2158-80. [PMID: 22652770 DOI: 10.2741/4043] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The neonatal rodent spinal cord maintained in vitro is a powerful model system to understand the central properties of spinal circuits generating mammalian locomotion. We describe three enabling approaches that incorporate afferent input and attached hindlimbs. (i) Sacral dorsal column stimulation recruits and strengthens ongoing locomotor-like activity, and implementation of a closed positive-feedback paradigm is shown to support its stimulation as an untapped therapeutic site for locomotor modulation. (ii) The spinal cord hindlimbs-restrained preparation allows suction electrode electromyographic recordings from many muscles. Inducible complex motor patterns resemble natural locomotion, and insights into circuit organization are demonstrated during spontaneous motor burst 'deletions', or following sensory stimuli such as tail and paw pinch. (iii) The spinal cord hindlimbs-pendant preparation produces unrestrained hindlimb stepping. It incorporates mechanical limb perturbations, kinematic analyses, ground reaction force monitoring, and the use of treadmills to study spinal circuit operation with movement-related patterns of sensory feedback while providing for stable whole-cell recordings from spinal neurons. Such techniques promise to provide important additional insights into locomotor circuit organization.
Collapse
Affiliation(s)
- Shawn Hochman
- Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.
| | | | | | | | | | | |
Collapse
|
|
15
|
Lin CY, Lee YS, Lin VW, Silver J. Fibronectin inhibits chronic pain development after spinal cord injury. J Neurotrauma 2012; 29:589-99. [PMID: 22022865 DOI: 10.1089/neu.2011.2059] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Chronic pain following spinal cord injury (SCI) is a highly prevalent clinical condition that is difficult to treat. Using both von Frey filaments and radiant infrared heat to assess mechanical allodynia and thermal hyperalgesia, respectively, we have demonstrated that a one-time injection of fibronectin (50 μg/mL) into the spinal dorsal column (1 μL/min each injection for a total of 5 μL) immediately after SCI inhibits the development of mechanical allodynia (but not thermal hyperalgesia) over an 8-month observation period following spinal cord dorsal column crush (DCC). DCC will only induce mechanical Allodynia, but not thermal hyperalgesia or overt motor deficits. By applying various fibronectin fragments as well as competitive inhibitors, these effects were shown to be dependent on the connecting segment-1 (CS-1) motif of fibronectin. Furthermore, we found that acute fibronectin treatment diminished inflammation and blood-spinal cord barrier permeability, which in turn leads to enhanced fiber sparing and sprouting. In particular, the reduction of serotonin (5-HT) in the superficial dorsal horn, an important descending brainstem system in the modulation of pain, was blocked with fibronectin treatment. We conclude that treatment of SCI with fibronectin preserves sensory regulation and prevents the development of chronic allodynia, providing a potential therapeutic intervention to treat chronic pain following SCI.
Collapse
Affiliation(s)
- Ching-Yi Lin
- Department of Neuroscience, Lerner Research Institute, Cleveland, Ohio 44195, USA.
| | | | | | | |
Collapse
|
|
16
|
Larauche M, Mulak A, Taché Y. Stress and visceral pain: from animal models to clinical therapies. Exp Neurol 2012; 233:49-67. [PMID: 21575632 PMCID: PMC3224675 DOI: 10.1016/j.expneurol.2011.04.020] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Revised: 04/07/2011] [Accepted: 04/28/2011] [Indexed: 02/07/2023]
Abstract
Epidemiological studies have implicated stress (psychosocial and physical) as a trigger of first onset or exacerbation of irritable bowel syndrome (IBS) symptoms of which visceral pain is an integrant landmark. A number of experimental acute or chronic exteroceptive or interoceptive stressors induce visceral hyperalgesia in rodents although recent evidence also points to stress-related visceral analgesia as established in the somatic pain field. Underlying mechanisms of stress-related visceral hypersensitivity may involve a combination of sensitization of primary afferents, central sensitization in response to input from the viscera and dysregulation of descending pathways that modulate spinal nociceptive transmission or analgesic response. Biochemical coding of stress involves the recruitment of corticotropin releasing factor (CRF) signaling pathways. Experimental studies established that activation of brain and peripheral CRF receptor subtype 1 plays a primary role in the development of stress-related delayed visceral hyperalgesia while subtype 2 activation induces analgesic response. In line with stress pathways playing a role in IBS, non-pharmacologic and pharmacologic treatment modalities aimed at reducing stress perception using a broad range of evidence-based mind-body interventions and centrally-targeted medications to reduce anxiety impact on brain patterns activated by visceral stimuli and dampen visceral pain.
Collapse
Affiliation(s)
- Muriel Larauche
- CURE/Digestive Diseases Research Center, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90073, USA.
| | | | | |
Collapse
|
|
17
|
Larauche M, Mulak A, Taché Y. Stress and visceral pain: from animal models to clinical therapies. Exp Neurol 2011. [PMID: 21575632 DOI: 10.1016/j.expneurol.2011.04.020.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Epidemiological studies have implicated stress (psychosocial and physical) as a trigger of first onset or exacerbation of irritable bowel syndrome (IBS) symptoms of which visceral pain is an integrant landmark. A number of experimental acute or chronic exteroceptive or interoceptive stressors induce visceral hyperalgesia in rodents although recent evidence also points to stress-related visceral analgesia as established in the somatic pain field. Underlying mechanisms of stress-related visceral hypersensitivity may involve a combination of sensitization of primary afferents, central sensitization in response to input from the viscera and dysregulation of descending pathways that modulate spinal nociceptive transmission or analgesic response. Biochemical coding of stress involves the recruitment of corticotropin releasing factor (CRF) signaling pathways. Experimental studies established that activation of brain and peripheral CRF receptor subtype 1 plays a primary role in the development of stress-related delayed visceral hyperalgesia while subtype 2 activation induces analgesic response. In line with stress pathways playing a role in IBS, non-pharmacologic and pharmacologic treatment modalities aimed at reducing stress perception using a broad range of evidence-based mind-body interventions and centrally-targeted medications to reduce anxiety impact on brain patterns activated by visceral stimuli and dampen visceral pain.
Collapse
Affiliation(s)
- Muriel Larauche
- CURE/Digestive Diseases Research Center, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90073, USA.
| | | | | |
Collapse
|
|
18
|
Borsook D, Becerra L. CNS animal fMRI in pain and analgesia. Neurosci Biobehav Rev 2011; 35:1125-43. [PMID: 21126534 PMCID: PMC3076623 DOI: 10.1016/j.neubiorev.2010.11.005] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2010] [Revised: 11/22/2010] [Accepted: 11/23/2010] [Indexed: 11/22/2022]
Abstract
Animal imaging of brain systems offers exciting opportunities to better understand the neurobiology of pain and analgesia. Overall functional studies have lagged behind human studies as a result of technical issues including the use of anesthesia. Now that many of these issues have been overcome including the possibility of imaging awake animals, there are new opportunities to study whole brain systems neurobiology of acute and chronic pain as well as analgesic effects on brain systems de novo (using pharmacological MRI) or testing in animal models of pain. Understanding brain networks in these areas may provide new insights into translational science, and use neural networks as a "language of translation" between preclinical to clinical models. In this review we evaluate the role of functional and anatomical imaging in furthering our understanding in pain and analgesia.
Collapse
Affiliation(s)
- David Borsook
- P.A.I.N. Group, Department of Radiology, Athinoula A. Center for Biomedical Imaging, Massachusetts General Hospital, 115 Mill Street, Belmont, MA 02478, United States.
| | | |
Collapse
|
|
19
|
Gosselin RD, Bebber D, Decosterd I. Upregulation of the GABA transporter GAT-1 in the gracile nucleus in the spared nerve injury model of neuropathic pain. Neurosci Lett 2010; 480:132-7. [PMID: 20542084 DOI: 10.1016/j.neulet.2010.06.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2010] [Revised: 06/03/2010] [Accepted: 06/04/2010] [Indexed: 01/26/2023]
Abstract
Neuropathic pain is a major health issue and is frequently accompanied by allodynia (painful sensations in response to normally non-painful stimulations), and unpleasant paresthesia/dysesthesia, pointing to alterations in sensory pathways normally dedicated to the processing of non-nociceptive information. Interestingly, mounting evidence indicate that central glial cells are key players in allodynia, partly due to changes in the astrocytic capacity to scavenge extracellular glutamate and gamma-aminobutyric acid (GABA), through changes in their respective transporters (EAAT and GAT). In the present study, we investigated the glial changes occurring in the dorsal column nuclei, the major target of normally innocuous sensory information, in the rat spared nerve injury (SNI) model of neuropathic pain. We report that together with a robust microglial and astrocytic reaction in the ipsilateral gracile nucleus, the GABA transporter GAT-1 is upregulated with no change in GAT-3 or glutamate transporters. Furthermore, [(3)H] GABA reuptake on crude synaptosome preparation shows that transporter activity is functionally increased ipsilaterally in SNI rats. This GAT-1 upregulation appears evenly distributed in the gracile nucleus and colocalizes with astrocytic activation. Neither glial activation nor GAT-1 modulation was detected in the cuneate nucleus. Together, the present results point to GABA transport in the gracile nucleus as a putative therapeutic target against abnormal sensory perceptions related to neuropathic pain.
Collapse
Affiliation(s)
- Romain-Daniel Gosselin
- Pain Research Unit, Department of Anesthesiology, University Hospital Center and University of Lausanne, Bugnon 46, 1011 Lausanne, Switzerland.
| | | | | |
Collapse
|
|
20
|
|
|
21
|
Williams MC, Ivanusic JJ. Evidence for the involvement of the spinoparabrachial pathway, but not the spinothalamic tract or post-synaptic dorsal column, in acute bone nociception. Neurosci Lett 2008; 443:246-50. [PMID: 18687382 DOI: 10.1016/j.neulet.2008.07.076] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2008] [Revised: 07/08/2008] [Accepted: 07/20/2008] [Indexed: 11/28/2022]
Abstract
We have previously reported that acute noxious mechanical stimulation of bone activates neurons throughout the dorsal horn of the lumbar spinal cord, and argued that the spinal mechanisms that mediate bone nociception are different to those that mediate cutaneous and visceral nociception. In the present study, we provide evidence that the ascending spinal pathways that mediate acute bone nociception also differ to those that mediate acute cutaneous and visceral nociception. Injections of a retrograde tracer (Fluorogold) were made into the thalamus, gracile nucleus or lateral parabrachial nucleus to identify spinothalamic, post-synaptic dorsal column or spinoparabrachial projection neurons respectively (n=4 in each group). Spinal dorsal horn neurons activated by acute noxious mechanical stimulation of bone (bone drilling) were identified in these animals using Fos immunohistochemistry. Fluorogold and Fos-like immunoreactivity was not colocalized in any dorsal horn neurons projecting to the thalamus or gracile nucleus. In contrast, a total of 12.2+/-1.1% (mean+/-S.E.M.) of the spinoparabrachial projection neurons contained Fos-like immunoreactive nuclei following bone drilling and this was significantly greater than the percentage (3.4+/-0.5%) in animals of a sham surgery group (n=4) that were not exposed to bone drilling (Mann-Whitney; p<0.05). These data provide evidence for the involvement of the spinoparabrachial pathway, but not the spinothalamic or post-synaptic dorsal column pathways, in the relay of information regarding acute noxious mechanical stimuli applied to bone, and suggest that spinal pathways that mediate acute bone nociception may be different to those that mediate acute nociception of cutaneous and visceral origin.
Collapse
Affiliation(s)
- Michael C Williams
- Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria 3010, Australia
| | | |
Collapse
|
|
22
|
Alioto OE, Lindsey CJ, Koepp J, Caous CA. Sensory sciatic nerve afferent inputs to the dorsal lateral medulla in the rat. Auton Neurosci 2008; 140:80-7. [PMID: 18514588 DOI: 10.1016/j.autneu.2008.04.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2007] [Revised: 04/11/2008] [Accepted: 04/15/2008] [Indexed: 12/18/2022]
Abstract
Investigations show the paratrigeminal nucleus (Pa5) as an input site for sensory information from the sciatic nerve field. Functional or physical disruption of the Pa5 alters behavioral and somatosensory responses to nociceptive hindpaw stimulation or sciatic nerve electrostimulation (SNS), both contralateral to the affected structure. The nucleus, an input site for cranial and spinal nerves, known for orofacial nociceptive sensory processing, has efferent connections to structures associated with nociception and cardiorespiratory functions. This study aimed at determining the afferent sciatic pathway to dorsal lateral medulla by means of a neuronal tract-tracer (biocytin) injected in the iliac segment of the sciatic nerve. Spinal cord samples revealed bilateral labeling in the gracile and pyramidal or cuneate tracts from survival day 2 (lumbar L1/L2) to day 8 (cervical C2/C3 segments) following biocytin application. From day 10 to day 20 medulla samples showed labeling of the contralateral Pa5 to the injection site. The ipsilateral paratrigeminal nucleus showed labeling on day 10 only. The lateral reticular nucleus (LRt) showed fluorescent labeled terminal fibers on day 12 and 14, after tracer injection to contralateral sciatic nerve. Neurotracer injection into the LRt of sciatic nerve-biocytin-treated rats produced retrograde labeled neurons soma in the Pa5 in the vicinity of biocytin labeled nerve terminals. Therefore, Pa5 may be considered one of the first sites in the brain for sensory/nociceptive inputs from the sciatic nerve. Also, the findings include Pa5 and LRt in the neural pathway of the somatosympathetic pressor response to SNS and nocifensive responses to hindpaw stimulation.
Collapse
|
|
23
|
Rinaman L. Visceral sensory inputs to the endocrine hypothalamus. Front Neuroendocrinol 2007; 28:50-60. [PMID: 17391741 PMCID: PMC1945046 DOI: 10.1016/j.yfrne.2007.02.002] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2006] [Revised: 02/14/2007] [Accepted: 02/14/2007] [Indexed: 02/07/2023]
Abstract
Interoceptive feedback signals from the body are transmitted to hypothalamic neurons that control pituitary hormone release. This review article describes the organization of central neural pathways that convey ascending visceral sensory signals to endocrine neurons in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus in rats. A special emphasis is placed on viscerosensory inputs to corticotropin releasing factor (CRF)-containing PVN neurons that drive the hypothalamic-pituitary-adrenal axis, and on inputs to magnocellular PVN and SON neurons that release vasopressin (AVP) or oxytocin (OT) from the posterior pituitary. The postnatal development of these ascending pathways also is considered.
Collapse
Affiliation(s)
- Linda Rinaman
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
| |
Collapse
|
|
24
|
Francisco AN, Lobão CAF, Sassaki VS, Garbossa MCP, Aguiar LR. [Punctate midline myelotomy for the treatment of oncologic visceral pain: analysis of three cases]. ARQUIVOS DE NEURO-PSIQUIATRIA 2007; 64:446-50. [PMID: 16917617 DOI: 10.1590/s0004-282x2006000300018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2005] [Accepted: 03/03/2006] [Indexed: 11/21/2022]
Abstract
INTRODUCTION A new midline posterior column pathway related to visceral pain has been recently discovered. OBJECTIVE To present its interruption by a punctate midline myelotomy providing significant visceral oncologic pain relief. METHOD Three patients with abdominal cancer refractory pain from opiate analgesics were treated by a punctate midline myelotomy through thoracic laminectomy. RESULTS Complete pain control was achieved in two patients, one had no more narcotics and the other one had significant lowering of opiate intake doses. The third patient was intolerant to narcotics having 80% relieving pain. There were no postoperative neurological deficits. CONCLUSION The present report reaffirms the existence of a dorsal column midline pathway related to visceral pain in humans, and its interruption ameliorates abdominal pain due to cancer.
Collapse
Affiliation(s)
- Alexandre N Francisco
- Serviço de Neurologia, Hospital Universitário Cajuru, Pontíficia Universidade Católica do Paraná, Hospital Universitário Cajuru, Av. São José 300, 80050-350 Curitiba PR, Brazil.
| | | | | | | | | |
Collapse
|
|
25
|
Anatomy of the Pain Processing System. Pain Manag 2007. [DOI: 10.1016/b978-0-7216-0334-6.50006-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] Open
|
|
26
|
Koehnle TJ, Rinaman L. Progressive postnatal increases in Fos immunoreactivity in the forebrain and brain stem of rats after viscerosensory stimulation with lithium chloride. Am J Physiol Regul Integr Comp Physiol 2006; 292:R1212-23. [PMID: 17082349 DOI: 10.1152/ajpregu.00666.2006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Interoceptive signals have a powerful impact on the motivation and emotional learning of animals during stressful experiences. However, current insights into the organization of interoceptive pathways stem mainly from observation and manipulation of adults, and little is known regarding the functional development of viscerosensory signaling pathways. To address this, we have examined central neural activation patterns in rat pups after treatment with lithium chloride (LiCl), a malaise-inducing agent. Rat pups were injected intraperitoneally with 0.15 M LiCl or 0.15 M NaCl (2% body wt) on postnatal day (P)0, 7, 14, 21, or 28, perfused 60 to 90 min postinjection, and their brains assayed for Fos protein immunolabeling. Compared with saline treatment, LiCl increased Fos only slightly in the area postrema, nucleus of the solitary tract, and lateral parabrachial nucleus on P0. LiCl did not increase Fos above control levels in the central nucleus of the amygdala, bed nucleus of the stria terminalis (BNST), or paraventricular nucleus of the hypothalamus on P0 but did on P7 and later. Maximal Fos responses to LiCl were observed on P14 in all areas except the BNST, in which LiCl-induced Fos activation continued to increase through P28. These results indicate that central LiCl-sensitive interoceptive circuits in rats are not fully functional at birth, and show age-dependent increases in neural Fos responses to viscerosensory stimulation with LiCl.
Collapse
Affiliation(s)
- Thomas J Koehnle
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
| | | |
Collapse
|
|
27
|
Andresen V, Camilleri M. Challenges in drug development for functional gastrointestinal disorders. Part II: visceral pain. Neurogastroenterol Motil 2006; 18:354-60. [PMID: 16629862 DOI: 10.1111/j.1365-2982.2006.00779.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
There is a need to have predictive biomarkers to test novel experimental medicines in functional gastrointestinal disorders. The human pharmacodynamic models and biomarkers pertaining to two important conditions are reviewed in a two-part article: functional dyspepsia (part I) and visceral pain (part II). With visceral pain models, the large coefficient of variation in sensation end points in human studies precludes definitive conclusions such as go/no go decisions or dose selection for phase IIb or III studies, unless very large numbers of patients are evaluated in phase IIA pharmacodynamic studies. This renders such pharmacological studies ambitious, or unachievable in a timely fashion. Moreover, the results of tests and clinical trials should be interpreted with greater knowledge of the drug pharmacokinetics, including the influence of CYP metabolism and potential drug interactions. Thus, it is important to identify valid biomarkers of visceral pain for the assessment of treatment response in pharmacodynamic studies. In this second part of a two-part article, we shall discuss the special challenges in developing medications for visceral pain and the general importance of including pharmacokinetic and pharmacogenomic studies in drug development programmes.
Collapse
Affiliation(s)
- V Andresen
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | | |
Collapse
|
|
28
|
Wree A, Itzev DE, Schmitt O, Usunoff KG. Neurons in the dorsal column nuclei of the rat emit a moderate projection to the ipsilateral ventrobasal thalamus. ACTA ACUST UNITED AC 2005; 210:155-62. [PMID: 16177909 DOI: 10.1007/s00429-005-0012-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/15/2005] [Indexed: 11/30/2022]
Abstract
The dorsal column nuclei (DCN; gracile and cuneate nuclei) give rise to the medial lemniscus, the fibre system that provides an organised somatosensory input to the thalamus. Unlike the spinothalamic and trigeminothalamic tracts that project, also to the ipsilateral thalamus, the medial lemniscus system is believed to be entirely crossed. We demonstrate that DCN emit a small number of axons that reach the ipsilateral thalamus. As retrograde fluorescent neuronal tracer Fluoro-gold was stereotaxically injected in the ventrobasal thalamus of nine young adult Wistar rats. The injection foci were voluminous and encroached upon adjacent nuclei, but the periphery of the injection halo never spilled over to the contralateral thalamus. All sections of the contralateral gracile and cuneate nuclei and the midline nucleus of Bischoff contained abundant retrogradely labelled neurons. The comparison with the Nissl-stained parallel sections suggests that approximately 70-80% of the DCN neurons project to the contralateral thalamus. Counting of retrogradely labelled neurons in two cases revealed 4,809 and 4,222 neurons in the contralateral and 265 and 214 in the ipsilateral DCN, respectively. Thus, although less prominent than the ipsilateral spinothalamic tract, the lemniscal system also emits an ipsilateral projection that accounts for about 5% of the neuronal population in DCN that innervates the ventrobasal thalamus.
Collapse
Affiliation(s)
- A Wree
- Institute of Anatomy, Faculty of Medicine, University of Rostock, Rostock, Germany.
| | | | | | | |
Collapse
|
|
29
|
Rinaman L, Schwartz G. Anterograde transneuronal viral tracing of central viscerosensory pathways in rats. J Neurosci 2004; 24:2782-6. [PMID: 15028771 PMCID: PMC6729508 DOI: 10.1523/jneurosci.5329-03.2004] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Previous studies demonstrated that strain H129 of herpes simplex virus-1 undergoes anterograde transneuronal transport in mice and primates after peripheral or central injection. In this study, H129 was used in rats to identify CNS regions that receive relayed viscero-sensory inputs from the stomach wall. We also examined whether transneuronal viral transport in this model is exclusively anterograde. H129 or an established retrograde transneuronal viral tracer, pseudorabies virus (PRV), was injected into the ventral stomach wall in intact rats or in rats with previous subdiaphragmatic vagal sensory deafferentation. Rats were perfused with fixative 3-5 d later, and tissues were processed for immunocytochemical detection of transported virus. In intact rats, H129 was transported transneuronally via vagal and spinal viscerosensory neurons to postsynaptic target cells in the medullary dorsal vagal complex and thoracic dorsal horn, respectively, with subsequent transport to discrete regions of the medullary and pontine reticular formation, cerebellum, parabrachial nucleus, periaqueductal gray, thalamus, hypothalamus, amygdala, bed nucleus of the stria terminalis, and other central sites. Comparison of labeling patterns in intact and vagal deafferented rats indicated that H129 also produced first-order retrograde infection of autonomic neurons that project directly to virus injection sites, similar to PRV. Unlike PRV, however, H129 was not transported transneuronally in the retrograde direction from infected neurons to central sources of presynaptic input. We conclude that transneuronal transport of H129 occurs exclusively in the anterograde direction to reveal CNS regions that receive direct and relayed viscerosensory signals.
Collapse
Affiliation(s)
- Linda Rinaman
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
| | | |
Collapse
|
|
30
|
Mönnikes H, Rüter J, König M, Grote C, Kobelt P, Klapp BF, Arnold R, Wiedenmann B, Tebbe JJ. Differential induction of c-fos expression in brain nuclei by noxious and non-noxious colonic distension: role of afferent C-fibers and 5-HT3 receptors. Brain Res 2003; 966:253-64. [PMID: 12618348 DOI: 10.1016/s0006-8993(02)04197-5] [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: 12/16/2022]
Abstract
Experimental animal models have been established to gain insight into the pathogenesis and the mechanisms of visceral hyperalgesia in the irritable bowel syndrome (IBS). However, data about the mechanisms and pathways involved in the induction of neuronal activity in forebrain and midbrain structures by a physiological GI stimulus, like colonic distension (CD), in the range from non-noxious to noxious intensities are scarce. Thus, the effect of proximal CD with non-noxious (10 mmHg) and noxious (40 and 70 mmHg) stimulus intensities on neuronal activity in brain nuclei, as assessed by c-fos expression, was established. In additional studies, the role of vagal and non-vagal afferent sensory C-fibers and 5-HT(3) receptors in the mediation of visceral nociception was investigated in this experimental model at noxious colonic distension (70 mmHg). At CD, the number of c-Fos like immunoreactivity (c-FLI)-positive neurons increased pressure-dependently in the nucleus of the solitary tract (NTS), rostral ventrolateral medulla (RVLM), nucleus cuneiformis (NC), periaqueductal gray (PAG), and the amygdala (AM). In the dorsomedial (DMH) and ventromedial nucleus (VMH) of the hypothalamus, as well as in the thalamus (TH), neuronal activity was also increased after CD, but independently of stimulus intensities. A decrease of the CD-induced c-fos expression after sensory vagal denervation by perivagal capsaicin treatment was only observed in brainstem nuclei (NTS and RVLM). In all other activated brain nuclei examined, the CD-related induction of c-fos expression was diminished only after systemic neonatal capsaicin treatment. In the NTS and RVLM, a trend of decrease of c-fos expression was also observed after systemic neonatal capsaicin treatment. In order to assess the role of the 5-HT(3) receptor in CD-induced neuronal activation of brain nuclei, animals were pretreated with the 5-HT(3) receptor antagonist granisetron (1250 microg/kg, i.p. within 18 h before CD). Pretreatment with granisetron significantly reduced the number of c-FLI-positive cells/section in the NTS by 40%, but had no significant effect on the CD-induced c-fos expression in other brain areas. The data suggest that distinct afferent pathways and transmitters are involved in the transmission of nociceptive information from the colon to the brain nuclei activated by proximal colonic distension. Activation of NTS neurons at such a condition seems to be partially mediated via capsaicin-sensitive vagal afferents and 5-HT(3) receptors. In contrast, activation of brain nuclei in the di- and telencephalon by nociceptive mechanical stimulation of the proximal colon, as assessed by c-fos expression, is partially mediated by capsaicin-sensitive, non-vagal afferents, and independent of neurotransmission via 5-HT(3) receptors. The modulation of CD-induced c-fos expression exclusively in the NTS by granisetron points to a role of 5-HT(3) receptor antagonists in the modulation of vago-vagal sensomotoric reflexes rather than an influence on forebrain nuclei involved in nociception.
Collapse
Affiliation(s)
- Hubert Mönnikes
- Department of Internal Medicine, Charité, Humboldt-Universität, Berlin, Germany.
| | | | | | | | | | | | | | | | | |
Collapse
|