Neuropathic pain, caused by peripheral or central nerve damage, and fibromyalgia, a chronic musculoskeletal disorder, require complex treatment approaches. This study evaluated the antiallodynic and antihyperalgesic effects of aripiprazole (1, 5, and 10 mg/kg, i. p.) in rats with chronic constriction injury-induced neuropathic pain and reserpine-induced fibromyalgia in female Sprague-Dawley rats, using electronic von Frey and Hargreaves tests. Dopaminergic, serotonergic, and opioidergic systems' roles were assessed through pre-treatment with sulpiride (50 mg/kg), WAY 100635 (1 mg/kg), and naloxone (1 mg/kg), respectively. The effect of aripiprazole was compared with 30 mg/kg pregabalin in the neuropathic pain model and 30 mg/kg duloxetine in the fibromyalgia model. Aripiprazole demonstrated significant antiallodynic and antihyperalgesic activity in both models. It did not change locomotor activity at a dose of 1 mg/kg but caused a decrease at a dose of 5 mg/kg. Dopamine D2, serotonin 5-HT1A, and opioidergic receptors contributed to aripiprazole's effects at varying levels. This study highlights the potential use of aripiprazole for managing neuropathic pain and fibromyalgia by targeting multiple receptor systems. The findings demonstrate the potential use of aripiprazole alone or as an adjuvant in the treatments of neuropathic pain and fibromyalgia.

Recent studies suggest that the nucleus accumbens (NAc) may influence the brain's response to pain signals, indicating a role beyond motivation and reward. The study delved into how the D1-like dopamine receptors (D1Rs) and μ-opioid receptors (MOR) interact in the NAc region in the context of formalin-induced pain. Rats received intra-accumbal various doses of morphine as an MOR agonist (5, 10, 25, and 50 mmol/0.5μl) and different doses of SKF38393 as a selective D1Rs agonist (1.5, 3, 6, and 12 mmol/0.5μl) in separate experimental groups, respectively. In the second stage, animals received different doses of SCH23390 as a selective D1Rs antagonist (1.5, 3, 6, and 12 mmol) before an effective dose of SKF38393 (6 mmol) and morphine (10 mmol). The rats were then given naloxone as an MOR antagonist (1.5, 5, and 15 mmol) before being given an effective dose of SKF38393 (6 mmol). In the formalin test, 50 µl formalin (2.5 %) was subcutaneously injected into the rat's hind paw to induce pain behavioral responses. The main findings indicated that the opioidergic and dopaminergic systems in the NAc region interact to create analgesic effects. The injection of morphine and SKF38393 into the NAc resulted in pain-relieving impacts. However, SCH23390 decreased the antinociceptive impacts of SKF38393 and morphine. Similarly, naloxone reduced the analgesic effects of SKF38393. The interactions between D1Rs and MOR can lead to synergistic effects. Therefore, using D1Rs agonists along with morphine can enhance the antinociceptive effect of morphine while reducing its side effects.

This study investigates changes in regional homogeneity (ReHo) of the brain in patients with adenomyosis accompanied by dysmenorrhea (AMD) before and after uterine artery embolization (UAE) surgery. ReHo is a resting-state functional magnetic resonance imaging (fMRI)-based analysis for assessing the temporal synchronization of local neuronal activity in the brain. This study involved 32 patients with AMD who underwent UAE surgery. Resting-state functional magnetic resonance imaging (fMRI) scans were performed before and after the procedure. A paired t-test analyzed ReHo images to identify significant changes across various brain regions. Each participant underwent relevant laboratory tests and was evaluated using pain and emotional scales. Correlation analyses were subsequently conducted to examine relationships between these clinical features and pre-treatment ReHo values in the identified brain regions. This study found that compared with pre-treatment, ReHo values decreased in the left hippocampus, left caudate nucleus, and left putamen, while increasing in the right paracentral lobule and right cuneus. Particularly, pre-treatment ReHo values in the left hippocampus were positively correlated with scores on the Visual Analog Scale (VAS), Hamilton Anxiety Rating Scale (HAMA), and Hamilton Depression Rating Scale (HAMD), suggesting that the left hippocampus plays an important role in the processing of pain and adverse emotions in AMD. These findings provide evidence for reversible central plasticity following pain relief in AMD, offering new insights into the neurobiological mechanisms of AMD, and may assist in developing more effective treatment strategies. PERSPECTIVE: This study identified significant changes in ReHo in several brain regions of AMD patients before and after treatment with UAE, especially the hippocampus was associated with preoperative pain level and related emotions, demonstrating that reversible central plasticity can occur after dysmenorrhea relief, which may help clinicians to formulate therapeutic strategies.

Clinical association studies have identified early life iron deficiency (ID) as a risk factor for the development of chronic pain. ID during the perinatal period has long-term consequences for the developing nervous system. Mounting evidence from both clinical and preclinical studies suggests that ID alters pain perception. However, nothing is yet known about how perinatal ID impacts nociceptive circuitry. The present study sought to characterize the effects of ID on the spinal superficial dorsal horn (SDH). Using ex vivo patch clamp electrophysiology in a mouse model of perinatal ID, the excitability of inhibitory and putative excitatory interneurons in the SDH was measured. It was found that early life ID did not significantly change the intrinsic excitability of either interneuron cell type in adolescence or adulthood. The investigation of synaptic inputs onto these two populations revealed that ID modulates spontaneous glutamatergic transmission within the SDH, but did not affect the excitatory drive or balance of synaptic excitation and inhibition. Interestingly, while ID altered the pattern of primary afferent inputs onto presumed glutamatergic interneurons in the mature SDH, the overall efficacy of these synapses was not affected by ID. Collectively, these results suggest that spinal nociceptive circuits are resilient to change following perinatal ID. PERSPECTIVE: This study demonstrates that perinatal iron deficiency (ID) elicits few changes to the intrinsic membrane excitability of superficial dorsal horn neurons or the efficacy of their synaptic inputs. These findings represent a critical first step towards elucidating the effects of ID on nociceptive processing in the central nervous system.

Recently, an old drug, disulfiram, has been shown to reduce cocaine intake by inhibiting dopamine beta (β)-hydroxylase. Its effectiveness was also reported in opioid treatment, as disulfiram attenuated morphine-induced tolerance and dependence. A similar mechanism of action was evident in a selective inhibitor of DβH, nepicastat, particularly in the aspect of cocaine-seeking behavior. Hence, the objective of this study was to verify whether or not nepicastat reproduces disulfiram activity in pain reduction. Moreover, determination of its likely biological effects resulting from interactions with targets other than DβH has been given, in particular acetylcholinesterase. As was found, nepicastat was characterized by the absence of desired antinociceptive activity, though its co-administration with morphine resulted in a dose- and time-dependent enhancement of morphine-induced analgesic effect and attenuation of tolerance. Similarly, nepicastat was found to manifest antimicrobial potency against selected bacterial strains, although the effect was found to be weak. Intriguingly, this compound interacted with acetylcholinesterase through inhibition of its activity. These results clearly indicate nepicastat as a potent molecule that exhibits various biological effects. This, in turn, suggests its possible application in pathological conditions that still require effective treatment.

Acute and chronic pain represents an escalating public health concern, necessitating safer and more effective in-hospital management approaches, including mental health. New treatment combinations involving psycholeptics are rising, but real-world evidence is lacking.

The study's primary objective is to evaluate the impact of combined opioid analgesics and antipsychotics in-hospital medication on pain modulation. The secondary objective is to evaluate pain management.

The cross-sequential study designed by this protocol will analyze retrospective data on 5,000 hospital admissions over four years (2019-2023) gathered from Electronic Health Records (EHR) of a multisite hospital in southern Switzerland. Eligible patients are aged 18 or older and hospitalized in an Internal Medicine ward. All patients with documented pain intensity assessment through a Visual Analogue Scale (VAS ≥ 1) will be included. Cross-sectional data on demographic and clinical variables and type of medication (opioid analgesics, antipsychotics, and selected other drugs according to the Anatomical Therapeutic Chemical classification system) will be screened at hospital admission (T1) and discharge (T2). Pain modulation will be assessed by gravity (VAS mean), intensity (VAS peak/extreme value), and pain treatment effectiveness (ΔT2-T1 VAS). Hospitalization paths (short- and long-term readmissions and total length of hospital stays) will be scrutinized as additional longitudinal indices for pain management and excluded from the cross-sectional analysis. A mixed model approach will assess VAS changes from T1 to T2. Logistic regression and regression models for count data will be used for short- and long-term readmission, respectively. Propensity score matching will be used to mitigate selection bias.

This methodological approach combines cross-sectional and longitudinal EHR data gathering in a cross-sequential design. This integration allows for a comprehensive examination of pain modulation and management among internal medicine recipients of concomitant opioids and antipsychotic treatment, spanning both hospitalization and post-discharge periods. By leveraging EHR data, the study protocol ensures reliability and standardization while minimizing missing information. Additionally, the protocol addresses the potential limitations of observational designs.

This method offers a comprehensive and rigorous approach to investigating pain modulation and management in internal medicine patients receiving combined opioid analgesics and antipsychotics, with potential implications for enhancing clinical practice and healthcare resource utilization.

Restless legs syndrome (RLS) is characterized by an urge to move with an unpleasant sensation in the lower limbs. RLS typically affects the legs. However, it can also affect several other body regions, such as the arms, abdomen, face, neck, head, and genital area. There are only a few reports of the RLS variant affecting the head.

To assess the epidemiological, clinical, and other aspects of the RLS variant affecting the head.

We conducted a retrospective study of 17 adult patients (> 18 years) who met the RLS criteria and simultaneously experienced RLS-like symptoms in the head.

The median age at which symptoms appeared was 41.6 years. Males and females were equally affected (1.1:1). All 17 patients had uncomfortable sensations in the lower legs. Insomnia or disturbed sleep was the most common comorbidity (n = 16, 88.2%). However, headache was the most common presenting or primary symptom (n = 10, 70.5%). Dizziness or an abnormal sensation in the head was the second most common presenting symptom (5 patients, 29.4%). Other presenting features were leg pain, backache, and generalized body pain. All patients responded favorably to dopaminergic medications.

If RLS-related unpleasant sensations and pain are felt in the head, they may be misinterpreted as headache, dizziness, or psychosomatic symptoms. RLS and headaches in a subset of patients may be two phenotypic manifestations of the same disorder.

Pain, or the ability to feel pain and express the unpleasantness caused by peripheral injuries, are functions of the central nervous system. From peripheral sensory nerve terminals to certain cortical regions of the brain, activation of related neural networks underlies the sensory process. Recently, our knowledge of pain has been increasing dramatically, due to the advancement of scientific approaches. We no longer see the brain as a random matrix for pain but, rather, we are able to identify the step-by-step selective signaling proteins, neurons, and networks that preferentially contribute to the process of chronic pain and its related negative emotions, like anxiety and fear. However, there is still lacking the selective and effective drugs and methods for the treatment of chronic pain clinically. While first-line drugs for acute pain and mental diseases are also applied for the clinical management of chronic pain, their prolonged usage always causes serious side effects. In this short review, we will update and summarize the recent progress in this field and mainly focus on the roles of neural networks and synaptic mechanisms in chronic neuropathic pain. Furthermore, potential drug targets (such as plasticity-related signaling molecules, ionic channels, cytokines, and neuropeptides) and methods for the management of chronic neuropathic pain will be discussed as well. We hope this review can provide new, valuable insight into the treatment of chronic neuropathic pain.

Chronic pain is an impeding condition that affects day-to-day life and poses a substantial economic burden, surpassing many other health conditions. This study employs a cross-species integrated approach to uncover novel pain mediators/regulators.

We used weighted gene coexpression network analysis to identify pain-enriched gene module. Functional analysis and protein-protein interaction (PPI) network analysis of the module genes were conducted. RNA sequencing compared pain model and control mice. PheWAS was performed to link genes to pain-related GWAS traits. Finally, candidates were prioritized based on node degree, differential expression, GWAS associations, and phenotype correlations.

A gene module significantly over-enriched with the pain reference set was identified (referred to as "pain module"). Analysis revealed 141 pain module genes interacting with 46 pain reference genes in the PPI network, which included 88 differentially expressed genes. PheWAS analysis linked 53 of these genes to pain-related GWAS traits. Expression correlation analysis identified Vdac1, Add2, Syt2, and Syt4 as significantly correlated with pain phenotypes across eight brain regions. NCAM1, VAMP2, SYT2, ADD2, and KCND3 were identified as top pain response/regulator genes.

The identified genes and molecular mechanisms may enhance understanding of pain pathways and contribute to better drug target identification.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles are the key players responsible for the pathogenesis of the disease. The accumulation of Aβ plaques and tau affect the balance in chemical neurotransmitters in the brain. Thus, the current review examined the role of neurotransmitters in the pathogenesis of Alzheimer's disease and discusses the alterations in the neurochemical activity and cross talk with their receptors and transporters. In the presence of Aβ plaques and neurofibrillary tangles, changes may occur in the expression of neuronal receptors which in turn triggers excessive release of glutamate into the synaptic cleft contributing to cell death and neuronal damage. The GABAergic system may also be affected by AD pathology in a similar way. In addition, decreased receptors in the cholinergic system and dysfunction in the dopamine neurotransmission of AD pathology may also contribute to the damage to cognitive function. Moreover, the presence of deficiencies in noradrenergic neurons within the locus coeruleus in AD suggests that noradrenergic stimulation could be useful in addressing its pathophysiology. The regulation of melatonin, known for its effectiveness in enhancing cognitive function and preventing Aβ accumulation, along with the involvement of the serotonergic system and histaminergic system in cognition and memory, becomes remarkable for promoting neurotransmission in AD. Additionally, nitric oxide and adenosine-based therapeutic approaches play a protective role in AD by preventing neuroinflammation. Overall, neurotransmitter-based therapeutic strategies emerge as pivotal for addressing neurotransmitter homeostasis and neurotransmission in the context of AD. This review discussed the potential for neurotransmitter-based drugs to be effective in slowing and correcting the neurodegenerative processes in AD by targeting the neurochemical imbalance in the brain. Therefore, neurotransmitter-based drugs could serve as a future therapeutic strategy to tackle AD.

To investigate the impact of music on patient tolerance during office-based laryngeal surgery (OBLS).

All patients undergoing OBLS between February 2024 to June 2024 were invited to participate in this study. They were divided into two subgroups, those with music in the background during surgery and those without. Following surgery, all patients were asked to fill IOWA tolerance score and the VAS for discomfort ranging from 0 to 10, with 0 indicating no discomfort and 10 indicating maximum discomfort.

A total of 87 patients undergoing 95 office-based laryngeal surgeries (OBLS) were included, with a mean age of 54.7 years and a male-to-female ratio of 1.5. The most common procedure was blue laser therapy (45.3%), followed by vocal fold injection (29.5%). The mean IOWA tolerance score was 2.02. Patients who listened to music during OBLS showed a significantly higher mean IOWA tolerance score compared to those without music (2.48 vs. 1.55; p < .001). Significant differences persisted when stratified by procedure type. Additionally, the mean VAS score for discomfort was lower with music (2.27 vs. 4.21; p = .001), with a significant difference noted for laser therapy (p = .004).

The results of this investigation indicate that music has a positive effect on procedural tolerance in OBLS. Participants who underwent OBLS with music in the background had significantly higher tolerance score and less discomfort than those who had no music in the background. Music can be used as a safe nonpharmacologic modality to reduce stress and improve patient tolerance in awake OBLS.

2.

Socioeconomic Position (SEP) is a multidimensional construct encompassing education, income, occupation, and neighborhood distress, influencing chronic pain severity, interference, and duration. However, its impact on placebo analgesia, where reduced pain perception occurs due to treatment belief, remains understudied. Using a quasi-experimental approach, we investigated SEP's influence on placebo analgesia in 401 participants with temporomandibular disorder (TMD) and 400 pain-free individuals. Using latent class analysis, we grouped participants into two SEP groups based on self-reported education, income, occupation, and neighborhood distress indices, including the area deprivation and distressed community indexes. Ancestry Informative Markers (AIMs) and self-reported race were included to account for genetic and demographic influences. Placebo analgesia was elicited using verbal suggestion and classical conditioning. Linear mixed models were employed to analyze SEP's impact, while multiple regression and ANCOVA assessed AIMs' and race's effects. Comparable placebo effects were observed between participants with TMD and pain-free individuals (F(1,4765.73) = 0.49, p = 0.48). A trend was noted in the main effect of SEP (F(1,4764.5) = 3.64, p = 0.056). Among TMD participants, those with distressed SEP exhibited lower placebo analgesia (F(1,4765.73) = 7.9, p = 0.005), while placebo response did not differ by SEP in pain-free participants (F(1,4765.73) = 0.27, p = 0.59). East Asian ancestry (β = 5.71, 95% CI [1.50, 9.92]) and self-reported Asian (mean = 24.20, sem = 1.52, p = 0.020) were associated with greater placebo analgesia. This study highlights the interplay of SEP, AIMs, and race in placebo analgesia and calls for tailored pain management interventions. PERSPECTIVE: SEP significantly contributes to pain disparities. This quasi-experimental study demonstrates analogous placebo analgesia between chronic pain and pain-free individuals but finds lower placebo analgesia only among individuals with chronic pain and distressed SEP. This highlights a link between chronic pain, SEP, and impaired placebo effects, suggesting new avenues for research.

The treatment of Burning Mouth Syndrome (BMS) represents a challenge in tailoring appropriate medication for individual patients. The augmentation of pregabalin to conventional treatment has shown promising outcomes in relieving pain and improving the quality of life in chronic pain conditions. This study aimed to compare the efficacy of vortioxetine with other antidepressants (SSRIs/SNRIs) in combination with pregabalin in a cohort of unresponsive BMS patients and to predict treatment response by using clinical data.

A 52-week randomized, open-label, comparative clinical study was conducted, enrolling 203 BMS patients previously treated with one antidepressant for 12 weeks and non-responders to the treatment (clinical trial registration: NCT06025474). The study sample included two groups: Group A (136) received vortioxetine, while Group B (67) received SSRIs/SNRIs. Pregabalin (75 mg/day) was added to both groups, with a potential dosage increase to 150 mg/day for inadequate responders after 12 weeks. Treatment response was assessed with VAS and SF-MPQ, HAM-A, and HAM-D scores at 12, 24, 36, and 52 weeks. Stepwise logistic regression analysis was used to predict treatment response.

A total of 84 (61.8%) BMS patients in Group A and 39 (58.2%) in Group B showed treatment response. Group A reported a faster onset of action compared to Group B (44.8% versus 22.4% at time 1; p:0.002**) and lower adverse event rates (8.8% versus 20.8%; p:0.001).

The addition of pregabalin to vortioxetine may be considered a potential treatment option for BMS. Further research is required to corroborate these findings and optimize personalized treatment approaches for BMS patients.

ClinicalTrials.gov (NCT06025474).

Persistent idiopathic facial pain (PIFP) can be challenging, both in its diagnosis, which appears to be purely exclusionary, and in its treatment, which currently lacks a gold standard. Amitriptyline is considered a first-line therapy, although not always effective. Recent insights into the role of dopamine in facial pain suggest that a novel therapeutic approach could target the dopamine system.

This study aimed to retrospectively evaluate the efficacy of treatment with amitriptyline-perphenazine association in patients with severe PIFP. Thirty-one patients were given a regimen dose of amitriptyline-perphenazine at dosages ranging between 10/2 and 20/4 mg and were then retrospectively analyzed. We evaluated the following outcomes, referred to the last week prior to follow-up visits: NRS score for pain intensity (minimum, maximum, and average), the number of attacks, and SF-36 questionnaire for quality of life. Comparisons were made between pre- and post-treatment.

Thirty-one patients over 35 were screened. At baseline, average NRS was 5 ± 0.93 (CI 95%: 4.6-5.3), and the median number of breakthrough episodes over last week was 5 ± 1.57 (CI 95%: 4-6) with a maximum NRS = 9 ± 0.89 (CI 95%: 8-9). After treatment, average NRS was 4.1 ± 0.93 (CI 95%: 3.8-4.5; p < 0.001), maximum NRS was 6.1 ± 1.60 (CI 95%: 5.5-6.6), and the median number of attacks was 4 ± 0.99 (IC 95%: 3-4) (p < 0.001). Regarding SF-36 questionnaire, the most improved parameters were quality of life related to pain (25.89 ± 12.48 vs 31.19 ± 13.44; p < 0.001) and physical function (69.56 ± 17.84 vs 84.17 ± 20.99; p < 0.001).

Despite limitations, the pain scores, the frequency of the attacks, and quality of life were found to be significantly improved after treatment. Although results are not broad based given the small sample size, the combination of amitriptyline and perphenazine may be an effective and well-tolerated treatment in patients with PIFP. It is abundantly clear that dopaminergic pathways play a key role in pain modulation, yet the underlying mechanisms have not been fully understood, requiring further investigation.

The single-nucleotide polymorphism (SNP) rs4680 in the catechol-O-methyltransferase gene ( COMT ) is a missense variant (Val158Met) associated with altered activity of the COMT enzyme and suggested as a predictive feature for developing some chronic pain conditions. However, there are controversial results on its role in fibromyalgia (FM). Here, the SNP Val158Met was analyzed in 294 FM patients (without comorbidities) and 209 healthy controls (without chronic pain). The concurrent impact of Val158Met genotypes and FM comorbid disorders (depression and sleep impairment) on FM risk were tested. In addition, the genotypic distribution of FM patients in relation to pain intensity was evaluated. The G allele (Val) resulted in being more represented in the FM group (57.8%) compared with the control group (48.8%; P = 0.037). Logistic regression highlighted that having the G/G (Val/Val) homozygous genotype was associated with 2 times higher risk of having FM compared with the A/A (Met/Met) carriers ( P = 0.038), whereas depression and sleep impairment increased FM risk by 12 and 8 times, respectively ( P < 0.001). However, considering only the FM patient group, the A/A homozygous genotype was significantly associated with severe pain intensity ( P = 0.007). This study highlighted associations between the SNP Val158Met and both FM and pain intensity, suggesting a link between dopaminergic dysfunction and vulnerability to chronic pain. Further studies should explore this SNP in FM patients in conjunction with COMT enzymatic activity and other symptoms connected with the dopaminergic system such as depression or sleep impairment.

This review delves into the intricate biological underpinnings of pain perception. It encompasses nociceptive signaling pathways, the molecular mechanisms involved, and the subjective experience of discomfort in humans. The initial focus is on nociceptor transduction, where specialized neurons transform noxious stimuli into electrical impulses. Subsequently, the review explores the central nervous system, elucidating how these signals are processed and modulated by critical elements such as ion channels, receptors, and neurotransmitters (e.g., substance P, glutamate, GABA). Shifting gears toward chronic pain, the review examines the concept of neuroplasticity, highlighting its potential to induce maladaptive responses through alterations in neural networks. The burgeoning field of pain genomics, alongside established genetic research, offers valuable insights that could pave the way for a framework of personalized pain management strategies. Finally, the review emphasizes the significance of these molecular insights in facilitating accurate therapeutic interventions. The overarching objective is to establish an integrative framework for precision medicine in pain management by incorporating this information alongside biopsychosocial models. This framework serves to translate the heterogeneous landscape of pain mechanisms into a coherent roadmap for the development of effective therapies.

Nociceptive pain perception is a remarkable capability of organisms to be aware of environmental changes and avoid injury, which can be accomplished by specialized pain receptors known as nociceptors with 4 vital properties including threshold, no adaptation, relaxation, and sensitization. Bioinspired systems designed using artificial devices are investigated to imitate the efficacy and functionality of nociceptive transmission. Here, an artificial pain-perceptual system (APPS) with a homogeneous material and heterogeneous integration is proposed to emulate the behavior of fast and slow pain in nociceptive transmission. Retention-differentiated poly[2-methoxy-5-(3,7-dimethyoctyoxyl)-1,4-phenylenevinylene] (MDMO-PPV) memristors with film thicknesses of 160 and 80 nm are manufactured and adopted as A-δ and C nerve fibers of nociceptor conduits, respectively. Additionally, a nociceptor mimic, the ruthenium nanoparticles (Ru-NPs)-doped MDMO-PPV piezoresistive pressure sensor, is fabricated with a noxiously stimulated threshold of 150 kPa. Under the application of pricking and dull noxious stimuli, the current flows predominantly through the memristor to mimic the behavior of fast and slow pain, respectively, in nociceptive transmission with postsynaptic potentiation properties, which is analogous to biological pain perception. The proposed APPS can provide potential advancements in establishing the nervous system, thus enabling the successful development of next-generation neurorobotics, neuroprosthetics, and precision medicine.

Autism spectrum disorder (ASD) is primarily characterized by core deficits in social skills, communication, and cognition and by repetitive stereotyped behaviors. These manifestations are variable between individuals, and ASD pathogenesis is complex, with over a thousand implicated genes, many epigenetic factors, and multiple environmental influences. The mesolimbic dopamine (DA) mediated brain reward system is held to play a key role, but the rapidly expanding literature reveals intricate, nuanced signaling involving a wide array of mesolimbic loci, neurotransmitters and receptor subtypes, and neuronal variants. How altered DA signaling may constitute a downstream convergence of the manifold causal origins of ASD is not well understood. A clear working framework of ASD pathogenesis may help delineate common stages and potential diagnostic and interventional opportunities. Hence, we summarize the known natural history of ASD in the context of emerging data and perspectives to update ASD reward signaling. Then, against this backdrop, we proffer a provisional framework that organizes ASD pathogenesis into successive levels, including (1) genetic and epigenetic changes, (2) disrupted mesolimbic reward signaling pathways, (3) dysregulated neurotransmitter/DA signaling, and finally, (4) altered neurocognitive and social behavior and possible antagonist/agonist based ASD interventions. This subdivision of ASD into a logical progression of potentially addressable parts may help facilitate the rational formulation of diagnostics and targeted treatments.

Chronic low back pain (cLBP) is a recurring and intractable disease that is often accompanied by emotional and cognitive disorders such as depression and anxiety. The nucleus accumbens (NAc) plays an important role in mediating emotional and cognitive processes and analgesia. This study investigated the resting-state functional connectivity (rsFC) and effective connectivity (EC) of NAc and its subregions in cLBP.

Thirty-four cLBP patients and 34 age- and sex-matched healthy controls (HC) underwent resting-state functional magnetic resonance imaging (rs-fMRI). Seed-based rsFC and Dynamic Causal Modelling (DCM) were used to examine the alteration of the rsFC and EC of the NAc.

Our results showed that the cLBP group had increased rsFC of the bilateral NAc-left superior frontal cortex (SFC), orbital frontal cortex (OFC), left angular gyrus, the left NAc-bilateral middle temporal gyrus, as well as decreased rsFC of left NAc-left supramarginal gyrus, right precentral gyrus, left cerebellum, brainstem (medulla oblongata), and right insula pathways compared with the HC; the results of the subregions were largely consistent with the whole NAc. In addition, the rsFC of the left NAc-left SFC was negatively correlated with Hamilton's Depression Scale (HAMD) scores (r = -0.402, p = 0.018), and the rsFC of left NAc-OFC was positively correlated with present pain intensity scores (r = 0.406, p = 0.017) in the cLBP group. DCM showed that the cLBP group showed significantly increased EC from the left cerebellum to the right NAc (p = 0.012) as compared with HC.

Overall, our findings demonstrate aberrant rsFC and EC between NAc and regions that are associated with emotional regulation and cognitive processing in individuals with cLBP, underscoring the pivotal roles of emotion and cognition in cLBP.

In modern times there is increasing acceptance that music-based interventions are useful aids in the clinical treatment of a range of neurological and psychiatric conditions, including helping to reduce the perception of pain. Indeed, the belief that music, whether listening or performing, can alter human pain experiences has a long history, dating back to the ancient Greeks, and its potential healing properties have long been appreciated by indigenous cultures around the world. The subjective experience of acute or chronic pain is complex, influenced by many intersecting physiological and psychological factors, and it is therefore to be expected that the impact of music therapy on the pain experience may vary from one situation to another, and from one person to another. Where pain persists and becomes chronic, aberrant central processing is a key feature associated with the ongoing pain experience. Nonetheless, beneficial effects of exposure to music on pain relief have been reported across a wide range of acute and chronic conditions, and it has been shown to be effective in neonates, children and adults. In this comprehensive review we examine the various neurochemical, physiological and psychological factors that underpin the impact of music on the pain experience, factors that potentially operate at many levels - the periphery, spinal cord, brainstem, limbic system and multiple areas of cerebral cortex. We discuss the extent to which these factors, individually or in combination, influence how music affects both the quality and intensity of pain, noting that there remains controversy about the respective roles that diverse central and peripheral processes play in this experience. Better understanding of the mechanisms that underlie music's impact on pain perception together with insights into central processing of pain should aid in developing more effective synergistic approaches when music therapy is combined with clinical treatments. The ubiquitous nature of music also facilitates application from the therapeutic environment into daily life, for ongoing individual and social benefit.

Cannabis has gained popularity in recent years as a substitute treatment for pain following the risks of typical treatments uncovered by the opioid crisis. The active ingredients frequently associated with pain-relieving effects are the phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), but their effectiveness and mechanisms of action are still under research. In this study, we used Caenorhabditis elegans, an ideal model organism for the study of nociception that expresses mammal ortholog cannabinoid (NPR-19 and NPR-32) and vanilloid (OSM-9 and OCR-2) receptors. Here, we evaluated the antinociceptive activity of THC and CBD, identifying receptor targets and several metabolic pathways activated following exposure to these molecules. The thermal avoidance index was used to phenotype each tested C. elegans experimental group. The data revealed for the first time that THC and CBD decreases the nocifensive response of C. elegans to noxious heat (32-35 °C). The effect was reversed 6 h post- CBD exposure but not for THC. Further investigations using specific mutants revealed CBD and THC are targeting different systems, namely the vanilloid and cannabinoid systems, respectively. Proteomic analysis revealed differences following Reactome pathways and gene ontology biological process database enrichment analyses between CBD or THC-treated nematodes and provided insights into potential targets for future drug development.

Corydalis Rhizome (RC) as a traditional analgesic Chinese medicine is the dried tuber of Corydalis yanhusuo W.T.Wang. Many efforts have revealed that RC could effectively alleviate neuropathic pain, while its active ingredients in neuropathic pain are still not clear.

Spinal central sensitization contributes greatly to neuropathic pain, and neuron, astrocyte and microglia play important roles in spinal central sensitization. The aim of the present study is to excavate active compounds in RC regulating spinal central sensitization to inhibit neuropathic pain.

Immunofluorescence and western blotting were used to determine protein expression levels. Gene expression levels were detected by RT-PCR. PC12 neuronal cells, C6 astrocyte cells, and BV2 microglia cells were cultured for in vitro studies. Targeting multi types of cells extraction combined with HPLC-Q-TOF-MS/MS was established to identify components binding to above cells. Animal studies were used to verify the analgesic activities of components.

Total alkaloids of RC (RC-TA) significantly relieved neuropathic pain in chronic constriction injury (CCI) rats and repressed spinal central sensitization. Eight components of RC-TA were found to bind to PC12, C6, or BV2 cells. They could respectively suppress the activation of cells in vitro and alleviate CCI-induced neuropathic pain, among which glaucine and dehydrocorydaline induced antinociception was stronger than l-THP. Meanwhile, glaucine had no effect on acute or chronic inflammatory pain, and its antinociception in neuropathic pain could be abolished by dopamine D1 receptor agonist.

Employing multi types of cells based on spinal central sensitization rather than single cell may allow for more thorough excavation of active substances. Glaucine was firstly found could attenuate neuropathic pain but not other types of pain which indicated that different alkaloids in RC exert distinct analgesic effects on different pain models, and gluacine has the potential to be developed as an analgesic drug specifically for neuropathic pain relieving.

The predictive coding theory is currently widely accepted as the theoretical basis of perception and chronic perceptual disorders are explained as the maladaptive compensation of the brain to a prediction error. Although this gives us a general framework to work with, it is still not clear who may be more susceptible and/or vulnerable to aberrations in this system. In this paper, we study changes in predictive coding through the lens of tinnitus and pain. We take a step back to understand how the predictive coding system develops from infancy, what are the different neural and bio markers that characterise this system in the acute, transition and chronic phases and what may be the factors that pose a risk to the aberration of this system. Through this paper, we aim to identify people who may be at a higher risk of developing chronic perceptual disorders as a reflection of aberrant predictive coding, thereby giving future studies more facets to incorporate in their investigation of early markers of tinnitus, pain and other disorders of predictive coding. We therefore view this paper to encourage the thinking behind the development of preclinical biomarkers to maladaptive predictive coding.

Pain is a major public health problem worldwide, with a high rate of treatment failure. Among promising non-pharmacological therapies, physical exercise is an attractive, cheap, accessible and innocuous method; beyond other health benefits. However, its highly variable therapeutic effect and incompletely understood underlying mechanisms (plausibly involving the GABAergic neurotransmission) require further research. This case-control study aimed to investigate the impact of long-lasting intensive endurance sport practice (≥7 h/week for the last 6 months at the time of the experiment) on the response to experimental cold-induced pain (as a suitable chronic pain model), assuming that highly trained individual would better resist to pain, develop advantageous pain-copying strategies and enhance their GABAergic signaling. For this purpose, clinical pain-related data, response to a cold-pressor test and high-density EEG high (Hβ) and low beta (Lβ) oscillations were documented. Among 27 athletes and 27 age-adjusted non-trained controls (right-handed males), a category of highly pain-resistant participants (mostly athletes, 48.1%) was identified, displaying lower fear of pain, compared to non-resistant non-athletes. Furthermore, they tolerated longer cold-water immersion and perceived lower maximal sensory pain. However, while having similar Hβ and Lβ powers at baseline, they exhibited a reduction between cold and pain perceptions and between pain threshold and tolerance (respectively -60% and - 6.6%; -179.5% and - 5.9%; normalized differences), in contrast to the increase noticed in non-resistant non-athletes (+21% and + 14%; +23.3% and + 13.6% respectively). Our results suggest a beneficial effect of long-lasting physical exercise on resistance to pain and pain-related behaviors, and a modification in brain GABAergic signaling. In light of the current knowledge, we propose that the GABAergic neurotransmission could display multifaceted changes to be differently interpreted, depending on the training profile and on the homeostatic setting (e.g., in pain-free versus chronic pain conditions). Despite limitations related to the sample size and to absence of direct observations under acute physical exercise, this precursory study brings into light the unique profile of resistant individuals (probably favored by training) allowing highly informative observation on physical exercise-induced analgesia and paving the way for future clinical translation. Further characterizing pain-resistant individuals would open avenues for a targeted and physiologically informed pain management.

A high incidence of attention-deficit hyperactivity disorder (ADHD) has been reported in chronic pain (ChP) patients. Furthermore, an association between ChP and muscular dysregulation has been reported in adults with ADHD. The present study investigated whether ADHD was more prevalent among psychiatric outpatients with ChP than those without ChP, and if there was an association between ChP, muscular dysregulation and characteristics of pain in patients with ADHD.

One-hundred and twenty-one individuals remitted to an outpatient psychiatry unit took part in this naturalistic epidemiological cross-sectional study. They were assessed with a pain self-report form (localization, intensity, and onset) and a test of muscle dysregulation (the Motor Function Neurological Assessment). Prevalence of ADHD among patients with ChP, as well as the qualitative characteristics of ChP within the ADHDgroup are reported. Both ChP and pain intensity correlated with muscular dysregulation through Spearman's rho analysis. Additionally, the relationship between various diagnostic categories (ADHD, affective disorders, anxiety, or personality disorders) and incidence of axial pain was evaluated in logistic regression.

ADHD was significantly more prevalent in patients with ChP, than in patients without ChP. In the ADHD group, ChP and pain intensity was associated with muscular dysregulation, particularly with high muscle tone. ChP was more axial and widespread, than for the patients without ADHD, and started at an early age. ADHD diagnosis predicted axial pain, whereas affective-, anxiety-, or personality disorders did not.

The study suggests that ChP in ADHD is associated with muscular dysregulation and is qualitatively different from ChP in psychiatric patients without ADHD. These findings may lead to further understanding of potential mechanisms involved in ADHD and ChP, and in turn to new treatment strategies for both disorders.

Parkinson's disease (PD) is the second most common neurodegenerative disease caused by the degeneration of dopaminergic neurons and the accumulation of Lewy bodies. Pain is one of the most common non-motor symptoms in PD, but the molecular mechanism of pain in PD is not fully understood, which prevents early diagnosis of PD. We aimed to determine the changes in opioidergic pathways when external pain is inflicted by inducing pain intraperitoneally in zebrafish, for which we generated a rotenone-induced PD model. After behavioural analyses in control(C), acetic acid (AA), rotenone (ROT), and rotenone+ acetic acid (ROT+AA) groups, catecholamine levels in brain tissue were determined by LC-MS/MS, expression of opioid peptides and their receptors by RT-PCR, expression of tyrosine hydroxylase by immunohistochemical method, and analyses of oxidant-antioxidant parameters by spectrophotometric methods. In the ROT group, distance travelled, average speed, and brain dopamine levels decreased, while LPO (lipid peroxidation) and NO (nitric oxide) increased as indicators of oxidative damage, and the SOD activity decreased. The mRNA expression of lrrk, pink1, and park7 genes associated with PD increased, while the mRNA expression of park2 decreased. This indicates that rotenone exposure is a suitable means to induce PD in zebrafish. The fact that body curvature was higher in the AA group than in the ROT and ROT+AA groups, as well as the decreased expression of penka, pdyn, and ion channels associated with the perception of peripheral pain in the ROT+AA group, suggest that mechanisms associated with pain are impaired in the rotenone-induced PD model in zebrafish.

Non-motor symptoms (NMS) of Parkinson's disease (PD) are well described in both clinical practice and the literature, enabling their management and enhancing our understanding of PD. NMS can dominate the clinical pictures and NMS subtypes have recently been proposed, initially based on clinical observations, and later confirmed in data driven analyses of large datasets and in biomarker-based studies. In this chapter, we provide an update on what is known about three common subtypes of NMS in PD. The pain (Park-pain), sleep dysfunction (Park-sleep), and autonomic dysfunction (Park-autonomic), providing an overview of their individual classification, clinical manifestation, pathophysiology, diagnosis, and potential treatments.

Pain is one of the most frequent non-motor symptoms of Parkinson's disease (PD). Neuropathic pain is highly prevalent in PD and negatively affects the quality of life of patients with PD. However, there is currently no evidence-based treatment for its control. Safinamide, a monoamine oxidase (MAO)-B inhibitor with a sodium channel inhibitory effect, showed improvement in PD-related pain in several clinical trials. However, it is unclear for which of the various types of pain in PD safinamide is effective. The aim of the present study was to examine the effect of safinamide on neuropathic pain in a rat model of chronic constriction injury (CCI). Pain was evaluated on postoperative days 14 and 21 using von Frey or weight-bearing tests. Male CCI model rats showed a decreased paw withdrawal threshold and a weight-bearing deficit on postoperative days 14 and 21. Single oral administration of safinamide (15, 30, 45 or 70 mg/kg) dose-dependently improved neuropathic pain in both pain assessments on day 14. Subsequently, the 15 and 45 mg/kg dose groups were administered safinamide orally once daily until day 21. With repeated administration, the effect of safinamide on pain was enhanced. The present findings show that safinamide improves neuropathic pain in male CCI model rats. Further animal model research and pathological and molecular pharmacological investigations are warranted.

Pain is an unpleasant sensory and emotional experience that affects every aspect of a patient's life and which may be treated through different pharmacological and non-pharmacological approaches. Analgesics are the drugs most commonly used to treat pain, and in specific situations, the use of opioids may be considered with caution. These drugs, in fact, do not always induce optimal analgesia in patients, and several problems are associated with their use. The purpose of this narrative review is to describe the pharmacological approaches currently used for the management of chronic pain. We review several aspects, from the pain-scale-based methods currently available to assess the type and intensity of pain, to the most frequently administered drugs (non-narcotic analgesics and narcotic analgesics), whose pharmacological characteristics are briefly reported. Overall, we attempt to provide an overview of different pharmacological treatments while also illustrating the relevant guidelines and indications. We then report the strategies that may be used to reduce problems related to opioid use. Specifically, we focus our attention on therapeutic drug monitoring (TDM), a tool that could help clinicians select the most suitable drug and dose to be used for each patient. The actual potential of using TDM to optimize and personalize opioid-based pain treatments is finally discussed based on recent scientific reports.

Persistent pain signals cause brain dysfunction and can further prolong pain. In addition, the physical restriction of movement (e.g., by a cast) can cause stress and prolong pain. Recently, it has been recognized that exercise therapy including rehabilitation is effective for alleviating chronic pain. On the other hand, physical stress and the restriction of movement can prolong pain. In this review, we discuss the neural circuits involved in the control of pain prolongation and the mechanisms of exercise-induced hypoalgesia (EIH). We also discuss the importance of the mesolimbic dopaminergic network in these phenomena.

Clinical association studies have identified early-life iron deficiency (ID) as a risk factor for the development of chronic pain. While preclinical studies have shown that early-life ID persistently alters neuronal function in the central nervous system, a causal relationship between early-life ID and chronic pain has yet to be established. We sought to address this gap in knowledge by characterizing pain sensitivity in developing male and female C57Bl/6 mice that were exposed to dietary ID during early life. Dietary iron was reduced by ∼90% in dams between gestational day 14 and postnatal day (P)10, with dams fed an ingredient-matched, iron-sufficient diet serving as controls. While cutaneous mechanical and thermal withdrawal thresholds were not altered during the acute ID state at P10 and P21, ID mice were more sensitive to mechanical pressure at P21 independent of sex. During adulthood, when signs of ID had resolved, mechanical and thermal thresholds were similar between early-life ID and control groups, although male and female ID mice displayed increased thermal tolerance at an aversive (45 °C) temperature. Interestingly, while adult ID mice showed decreased formalin-induced nocifensive behaviors, they showed exacerbated mechanical hypersensitivity and increased paw guarding in response to hindpaw incision in both sexes. Collectively, these results suggest that early-life ID elicits persistent changes in nociceptive processing and appears capable of priming developing pain pathways. PERSPECTIVE: This study provides novel evidence that early-life ID evokes sex-independent effects on nociception in developing mice, including an exacerbation of postsurgical pain during adulthood. These findings represent a critical first step towards the long-term goal of improving health outcomes for pain patients with a prior history of ID.

Pain disrupts sleep, and sleep deprivation or interference can alter pain perception in animals and humans, for example by increasing sensitivity to pain. However, the mechanism by which sleep affects neuropathic pain remains unclear. In this review, we discuss the available evidence from the epidemiologic, clinical, and human, as well as laboratory studies. In previous studies, we have found that sleep deprivation affects various injurious systems, including opioids, dopaminergic, immune, orexins, hypothalamic-pituitary-adrenal axis, and adenosine. At the same time, these systems play a crucial role in neuropathic pain regulation. In the complex interactions between these neurobiological systems, there may be potential regulatory pathways through which sleep deprivation amplifies neuropathic pain. Because of the impact sleep problems and neuropathic pain can have on the patients' quality of life, studying the link between sleep and neuropathic pain is important for neuropathic pain prevention and public health.

Burning mouth disorder (BMD) is a complex medical condition characterized by a burning sensation in the mouth of fluctuating intensity. BMD is considered a diagnosis of exclusion, as oral burning can occur secondary to local or systemic conditions. Parkinson's disease (PD) is one such condition.

To provide a scoping review of the literature by assessing all articles written in English that investigated the relationship between BMD and PD.

Various databases (PubMed, Ovid, Web of Science, Science Direct and Scopus) and a search platform (EBSCOhost) were searched following similar investigative approaches. Duplicates were removed and reference lists of original studies were scrutinized for additional articles. Any decision about the inclusion/exclusion in the review was by consensus among the co-authors.

Twenty-five original articles and one supplemental article were included in the final review, of which 13 met the inclusion criteria. These were further divided into five categories based on the study design/article, which included Prevalence studies (n = 6), Letter to the editor (n = 1), Incidence study (n = 1), Case reports (n = 2) and Experimental studies (n = 3). Strongest data was provided by epidemiological studies, which suggest BMD and PD are poorly associated.

A scoping review of the existing literature does not suggest that PD patients are any more at risk of developing BMD compared to the general population. While there may be a link through the dopaminergic system as determined by imaging studies, it is unlikely that the pathogenesis of PD disease shares significant commonality with BMD.

It has been declared that dopamine receptors within the hippocampal formation are involved in emotion, memory, and pain processing. Remarkably, both CA1 and dentate gyrus (DG) areas of the hippocampal formation are involved in persistent peripheral nociceptive perception. A prior study showed that dopamine receptors within the hippocampal DG have a critical role in antinociception induced by forced swim stress (FSS), as a physical stressor, in the presence of formalin irritation. The present experiments were designed to assess whether dopaminergic receptors within the CA1 have any role in antinociceptive responses induced by restraint stress (RS) as a psychological stressor after applying the formalin test as an animal model of persistent inflammatory pain. The D1- and D2-like dopamine receptor antagonists, SCH23390 and Sulpiride (0.25, 1, and 4 μg/0.5 μl), were injected into the CA1 areas of ninety-six male albino Wistar rats 5 min before a 3-h period of restraint stress. Ten min after stress termination, a 50-μl formalin 2.5 % was subcutaneously injected into the plantar surface of the rat's hind paw to induce persistent inflammatory pain. Nociceptive behaviors in both phases of the formalin test were analyzed in the 5-min blocks for a 60-min period. The obtained results demonstrate that although RS could induce an antinociceptive response in both phases of the formalin test, microinjection of D1- and D2-like dopamine receptors, antagonists attenuated RS-induced analgesia. These results support the hypothesis that acute restraint stress could induce analgesia via dopaminergic projection to the CA1 region of the hippocampal formation.

New strategies facilitate the design of cyclic peptides which can penetrate the brain. We have designed a bicyclic peptide, OL-CTOP, composed of the sequences of a selective μ-opioid receptor antagonist, CTOP (f-cyclo(CYwOTX)T) (X = penicillamine, Pen; O = ornithine) and odorranalectin, OL (YASPK-cyclo(CFRYPNGVLAC)T), optimized its solid-phase synthesis and demonstrated its ability for nose-to-brain delivery and in vivo activity. The differences in reactivity of Cys and Pen thiol groups protected with trityl and/or acetamidomethyl protecting groups toward I2 in different solvents were exploited for selective disulfide bond formation on the solid phase. Both the single step and the sequential strategy applied to macrocyclization reactions generated the desired OL-CTOP, with the sequential strategy yielding a large quantity and better purity of crude OL-CTOP. Importantly, intranasally (i.n.s.) administered OL-CTOP dose-dependently antagonized the analgesic effect of morphine administered to mice through the intracerebroventricular route and prevented morphine-induced respiratory depression. In summary, the results demonstrate the feasibility of our solid-phase synthetic strategy for the preparation of the OL-CTOP bicyclic peptide containing two disulfide bonds and reveal the potential of odorranalectin for further modifications and the targeted delivery to the brain.

Chronic pain is a refractory health disease worldwide causing an enormous economic burden on individuals and society. Accumulating evidence suggests that inflammation in the peripheral nervous system (PNS) and central nervous system (CNS) is the major factor in the pathogenesis of chronic pain. The inflammation in the early- and late phase may have distinctive effects on the initiation and resolution of pain, which can be viewed as friend or foe. On the one hand, painful injuries lead to the activation of glial cells and immune cells in the PNS, releasing pro-inflammatory mediators, which contribute to the sensitization of nociceptors, leading to chronic pain; neuroinflammation in the CNS drives central sensitization and promotes the development of chronic pain. On the other hand, macrophages and glial cells of PNS and CNS promote pain resolution via anti-inflammatory mediators and specialized pro-resolving mediators (SPMs). In this review, we provide an overview of the current understanding of inflammation in the deterioration and resolution of pain. Further, we summarize a number of novel strategies that can be used to prevent and treat chronic pain by controlling inflammation. This comprehensive view of the relationship between inflammation and chronic pain and its specific mechanism will provide novel targets for the treatment of chronic pain.

The outcomes of pain and stress in preterm infants in the neonatal intensive care units (NICUs) compel the continued search for pain- and stress-reducing interventions.

To investigate how skin-to-skin contact (SSC) influences chronic pain and stress in preterm infants in the NICU.

The study included 140 preterm infants in the NICU with gestational age less than 34 weeks. The overall design was a baseline-response design. Urine and saliva were collected before (baseline) and after SSC to measure pain and stress markers by enzyme immunoassay method. The behavioral indicators of chronic pain were assessed using the EDIN (Échelle Douleur Inconfort Nouveau-Né-neonatal pain and discomfort).

There was a significant decrease in the dopamine level in preterm infants after SSC in comparison with baseline values (85.99 [69.35; 112.20] pg/ml vs. 132.20 [104.80; 183.70] pg/ml), p < 0.001. The β-endorphin and serotonin levels increased after SSC (40.09 [26.81; 70.63] pg/ml vs. 29.87 [20.61; 46.94] pg/ml, p = 0.009 and 25.49 [20.45; 40.08] ng/ml vs. 22.30 [15.13; 31.65] ng/ml, p = 0.011, respectively). A significant decrease in cortisol levels in saliva and urine after SSC in comparison with baseline values (0.125 [0.079; 0.225] μg/dl vs. 0.371 [0.188; 1.002] μg/dl, p = 0.000 and 27.06 [14.59; 35.35] ng/ml vs. 35.25 [19.78; 61.94] ng/ml, p = 0.001, with a simultaneous increase of oxytocin level (57.00 [36.55; 88.49] pg/ml vs. 38.20 [28.78; 56.04] pg/ml, p = 0.009 were revealed. The total pain EDIN score in infants after SSC was below 6 points, significantly decreasing compared to the baseline (p < 0.05).

Preterm infants in the NICU experience stress and pain, which were confirmed by the EDIN pain scale and laboratory markers. The level of dopamine and cortisol as pain and stress hormones were reliably high, and normalized after regular SSC. Simultaneously, pain-relieving and anti-stress markers of oxytocin, β-endorphin and serotonin reliably increased in preterm infants in response to the SSC.

Pain is a representative non-motor symptom in patients with Parkinson's disease (PD). Pain is one of the most common symptoms that plague patients with PD regardless of the stage of the disease, also it can exacerbate other symptoms, such as depression, anxiety or sleep disturbance, and lead to impaired quality of life. However, pain is often not adequately evaluated and treated. PD patients complain of a wide variety of pain, including both PD-related pain which caused by PD-specific symptoms, for example, rigidity, bradykinesia or motor fluctuation, and PD-unrelated pain, and it can be divided into central and peripheral depending on the site of the disorder. In the medical care of the pain, it is important to evaluate the type and severity of the pain using PD-specific assessment scales such as King's PD pain scale and to consider the evidence-based treatment methods according to the pathophysiology of the pain.

The nervous system is a vital part of organisms to survive and it endows them with remarkable abilities, such as perception, recognition, regulation, learning, and decision-making, by intertwining myriad neurons. To realize such outstanding efficacies and functions, many artificial devices and systems have been investigated to emulate the operating principles of the nervous system. Here, an artificial reflex arc (ARA) and artificial pain modulation system (APMS) are proposed to imitate the unconscious behaviors of the spinal cord. Gd_x O_y - and Al_x O_y -based charge-regulated field-effect transistors (CRFETs) with a monolayer graphene channel are fabricated and adopted as inhibitory and excitatory synapses, respectively, under the same pulse signals to mimic the biological reflex arc through a connection with a poly(vinylidene fluoride-co-trifluoroethylene)-based actuator. Additionally, a memristor is integrated with a CRFET as the interneuron to regulate the Dirac point by controlling the voltage drop on the graphene channel, analogous to the descending pain-inhibition system in the spinal cord, to prevent excessive pain perception. The proposed ARA and APMS provide a significant step forward to realizing the functions of the nervous system, giving promising potential for developing future intelligent alarm systems, neuroprosthetics, and neurorobotics.