Descending Pain Inhibitory Pathways Research Articles

Sex differences in visceral sensitivity and brain activity in a rat model of comorbid pain: a longitudinal study.

Temporomandibular disorder (TMD) and irritable bowel syndrome (IBS) are 2 chronic overlapping pain conditions (COPCs) that present with significant comorbidity. Both conditions are more prevalent in women and are exacerbated by stress. While peripheral mechanisms might contribute to pain hypersensitivity for each individual condition, mechanisms underlying the comorbidity are poorly understood, complicating pain management when multiple conditions are involved. In this study, longitudinal behavioral and functional MRI-based brain changes have been identified in an animal model of TMD-like pain (masseter muscle inflammation followed by stress) that induces de novo IBS-like comorbid visceral pain hypersensitivity in rats. In particular, data indicate that increased activity in the insula and regions of the reward and limbic systems are associated with more pronounced and longer-lasting visceral pain behaviors in female rats, while the faster pain resolution in male rats may be due to increased activity in descending pain inhibitory pathways. These findings suggest the critical role of brain mechanisms in chronic pain conditions and that sex may be a risk factor of developing COPCs.

PAIN THRESHOLD PARADOX IN SCHIZOPHRENIA: A NARRATIVE REVIEW BASED ON THE LASTEST NEUROSCIENCE.

Pain is one of the basic defense responses of living organisms. Although the threshold for pain perception varies from person to person, there is no doubt that pain reduces a person's quality of life. Assessing the subjective experience of pain is especially important in the treatment of patients with schizophrenia. In light of recent advances in neuroscience, we discuss pain thresholds in patients with schizophrenia. A narrative review of pain thresholds in patients with schizophrenia was conducted. We electronically searched the PubMed and Google Scholar databases for articles in English with "pain," "schizophrenia," "neural circuits," and "neurotransmitters" in the title or abstract, for the period January 2000 through June 2022. A seemingly contradictory phenomenon has been noted with regard to pain thresholds in patients with schizophrenia. One phenomenon is a high pain threshold for nociceptive stimuli, and the other is a low pain threshold in chronic pain. As a result, a pain threshold paradox has been observed. Many schizophrenia patients appear to have an excess of dopamine in the mesolimbic system, which stimulates both the descending pain inhibitory pathway and the salience network. As a result, a pain threshold paradox has been observed, in which the threshold for acute nociceptive pain is high and the threshold for chronic pain is low.

Essential roles of the hypothalamic A11 region and the medullary raphe nuclei in regulation of colorectal motility in rats.

The supraspinal brain regions controlling defecation reflex remain to be elucidated. The purpose of this study was to determine the roles of the hypothalamic A11 region and the medullary raphe nuclei in regulation of defecation. For chemogenetic manipulation of specific neurons, we used the double virus vector infection method in rats. hM3Dq or hM4Di was expressed in neurons of the A11 region and/or the raphe nuclei that send output to the lumbosacral defecation center. Immunohistological and functional experiments revealed that both the A11 region and the raphe nuclei directly connected with the lumbosacral spinal cord through descending pathways composed of stimulatory monoaminergic neurons. Stimulation of the hM3Dq-expressing neurons in the A11 region or the raphe nuclei enhanced colorectal motility only when GABAergic transmission in the lumbosacral spinal cord was blocked by bicuculline. Experiments using inhibitory hM4Di-expressing rats revealed that enhancement of colorectal motility caused by noxious stimuli in the colon is mediated by both the A11 region and the raphe nuclei. Furthermore, suppression of the A11 region and/or the raphe nuclei significantly inhibited water avoidance stress-induced defecation. These findings demonstrate that the A11 region and the raphe nuclei play an essential role in regulation of colorectal motility. This is important because brain regions that mediate both intracolonic noxious stimuli-induced defecation and stress-induced defecation have been clarified for the first time.

Activation of Cannabinoid Receptor 1 in GABAergic Neurons in the Rostral Anterior Insular Cortex Contributes to the Analgesia Following Common Peroneal Nerve Ligation

The rostral agranular insular cortex (RAIC) has been associated with pain modulation. Although the endogenous cannabinoid system (eCB) has been shown to regulate chronic pain, the roles of eCBs in the RAIC remain elusive under the neuropathic pain state. Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve (CPN) ligation. The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice, glutamatergic, or GABAergic neuron cannabinoid receptor 1 (CB1R) knockdown mice with the whole-cell patch-clamp and pain behavioral methods. The E/I ratio (amplitude ratio between mEPSCs and mIPSCs) was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice. Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice. The analgesic effect of ACEA (a CB1R agonist) was alleviated along with bilateral dorsolateral funiculus lesions, with the administration of AM251 (a CB1R antagonist), and in CB1R knockdown mice in GABAergic neurons, but not glutamatergic neurons of the RAIC. Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.

Targeting Neuroinflammation with Abscisic Acid Reduces Pain Sensitivity in Females and Hyperactivity in Males of an ADHD Mice Model.

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome characterized by dopaminergic dysfunction. In this study, we aimed to demonstrate that there is a link between dopaminergic deficit and neuroinflammation that underlies ADHD symptoms. We used a validated ADHD mice model involving perinatal 6-OHDA lesions. The animals received abscisic acid (ABA), an anti-inflammatory phytohormone, at a concentration of 20 mg/L (drinking water) for one month. We tested a battery of behavior tests, learning and memory, anxiety, social interactions, and pain thresholds in female and male mice (control and lesioned, with or without ABA treatment). Postmortem, we analyzed microglia morphology and Ape1 expression in specific brain areas related to the descending pain inhibitory pathway. In females, the dopaminergic deficit increased pain sensitivity but not hyperactivity. In contrast, males displayed hyperactivity but showed no increased pain sensitivity. In females, pain sensitivity was associated with inflammatory microglia and lower Ape1 levels in the anterior cingulate cortex (ACC) and posterior insula cortex (IC). In addition, ABA treatment alleviated pain sensitivity concomitant with reduced inflammation and normalized APE1. In males, ABA reduced hyperactivity but had no significant effect on inflammation in these areas. This is the first study proving a sex-dependent association between dopamine dysfunction and inflammation in specific brain areas, hence leading to different behavioral outcomes in a mouse model of ADHD. These findings provide new clues for potential treatments for ADHD.

Sex differences in the central regulation of colorectal motility in response to noxious stimuli.

Distinct sex differences in the prevalence and symptoms of abnormal bowel habits in patients with irritable bowel syndrome (IBS) have been reported. We have elucidated the sex differences in the regulation of colorectal motility via the central nervous system. Noxious stimuli in the colorectum of anesthetized male rats enhance colorectal motility by activating monoaminergic neurons in descending pain inhibitory pathways from the brainstem to the lumbosacral spinal cord. These monoaminergic neurons release serotonin and dopamine into the lumbosacral spinal cord, resulting in the increment of colorectal motility. In female rats, in contrast, noxious stimuli in the colorectum have no effect on colorectal motility. We clarified that GABAergic inhibition in the lumbosacral spinal cord masks the enhancement of colorectal motility induced by monoamines in female animals. Considering that IBS patients often show visceral hypersensitivity and hyperalgesia, our studies suggest that differences in the descending neurons that respond to painful stimuli are involved in various sex differences in abnormal bowel habits.

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

Diffuse noxious inhibitory controls and conditioned pain modulation: a shared neurobiology within the descending pain inhibitory system?

The effect of duloxetine on mechanistic pain profiles, cognitive factors and clinical pain in patients with painful knee osteoarthritis-A randomized, double-blind, placebo-controlled, crossover study.

BackgroundDuloxetine is indicated in the management of pain in osteoarthritis. Evidence suggests that duloxetine modulates central pain mechanisms and cognitive factors, and these factors are assumed contributing to the analgesic effect. This proof‐of‐mechanism, randomized, placebo‐controlled, crossover, double‐blinded trial evaluated the effect of duloxetine on quantitative sensory testing (QST), cognitive factors and clinical pain in patients with osteoarthritis and to predict the analgesic effect.MethodsTwenty‐five patients completed this cross‐over study with either 18‐week duloxetine (maximum 60 mg/daily) followed by placebo or vice‐versa. Pressure pain thresholds, temporal summation of pain and conditioned pain modulation were assessed using cuff algometry. The Hospital Anxiety and Depression Scale and the Pain Catastrophizing Scale evaluated cognitive factors. Clinical pain was assessed using Brief Pain Inventory and Western Ontario and McMaster Universities Osteoarthritis Index. Linear regression models were used to predict the analgesic effect of duloxetine.ResultsDepending on the clinical pain outcome, 40%–68% of patients were classified as responders to duloxetine. Linear regression models predicted the analgesic effect (predictive value of 45%–75% depending on clinical pain outcome parameter) using a combination of pretreatment QST parameters, cognitive factors and clinical pain. No significant changes were found for QST, cognitive factors or clinical pain on a group level when comparing duloxetine to placebo.ConclusionA combination of pretreatment QST, cognitive factors and clinical pain was able to predict the analgesic response of duloxetine. However, in this relatively small study, duloxetine did not selectively modulate QST, cognitive factors or clinical pain intensity when compared with placebo.SignificanceDuloxetine is proposed as a treatment for chronic pain. Pre‐clinical trials suggest that duloxetine provides analgesia through modulation of descending pain inhibitory pathways or through improvements in cognitive factors. The current study demonstrates that pretreatment mechanistic pain profiling, cognitive factors and clinical pain can predict the analgesic effect of duloxetine and that only a subset of patients might benefit from duloxetine treatment.

The mechanism of action of pulsed radiofrequency in reducing pain: a narrative review

Pain from nervous or musculoskeletal disorders is one of the most common complaints in clinical practice. Corticosteroids have a high pain-reducing effect, and their injection is generally used to control various types of pain. However, they have various adverse effects including flushing, hyperglycemia, allergic reactions, menstrual changes, immunosuppression, and adrenal suppression. Pulsed radiofrequency (PRF) is known to have a pain-reducing effect similar to that of corticosteroid injection, with nearly no major side effects. Therefore, it has been widely used to treat various types of pain, such as neuropathic, joint, discogenic, and muscle pain. In the current review, we outlined the pain-reducing mechanisms of PRF by reviewing previous studies. When PRF was first introduced, it was supposed to reduce pain by long-term depression of pain signaling from the peripheral nerve to the central nervous system. In addition, deactivation of microglia at the level of the spinal dorsal horn, reduction of proinflammatory cytokines, increased endogenous opioid precursor messenger ribonucleic acid, enhancement of noradrenergic and serotonergic descending pain inhibitory pathways, suppression of excitation of C-afferent fibers, and microscopic damage of nociceptive C- and A-delta fibers have been found to contribute to pain reduction after PRF application. However, the pain-reducing mechanism of PRF has not been clearly and definitely elucidated. Further studies are warranted to clarify the pain-reducing mechanism of PRF.

Alternative pain management via endocannabinoids in the time of the opioid epidemic: Peripheral neuromodulation and pharmacological interventions.

The use of opioids in pain management is hampered by the emergence of analgesic tolerance, which leads to increased dosing and side effects, both of which have contributed to the opioid epidemic. One promising potential approach to limit opioid analgesic tolerance is activating the endocannabinoid system in the CNS, via activation of CB1 receptors in the descending pain inhibitory pathway. In this review, we first discuss preclinical and clinical evidence revealing the potential of pharmacological activation of CB1 receptors in modulating opioid tolerance, including activation by phytocannabinoids, synthetic CB1 receptor agonists, endocannabinoid degradation enzyme inhibitors, and recently discovered positive allosteric modulators of CB1 receptors. On the other hand, as non-pharmacological pain relief is advocated by the US-NIH to combat the opioid epidemic, we also discuss contributions of peripheral neuromodulation, involving the electrostimulation of peripheral nerves, in addressing chronic pain and opioid tolerance. The involvement of supraspinal endocannabinoid systems in peripheral neuromodulation-induced analgesia is also discussed. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Mesenchymal Stem Cell Sheet Promotes Functional Recovery and Palliates Neuropathic Pain in a Subacute Spinal Cord Injury Model.

Stem cell therapy has been shown to reverse the sequelae of spinal cord injury (SCI). Although the ideal treatment route remains unknown, providing a large number of stem cells to the injured site using less invasive techniques is critical to achieving maximal recovery. This study was conducted to determine whether administration of bone marrow stem cell (BMSC) sheet made on its own without a scaffold is superior to intramedullary cell transplantation in a rat subacute SCI model. Adult female Sprague-Dawley rats were subjected to SCI by 30 g clip compression at the level of Th6 and Th7 and were administered BMSC cell sheet (7 × 104 cells, subdural), cell suspension (7 × 104 cells, intramedullary), or control seven days after the injury. Motor and sensory assessments, as well as histological evaluation, were performed to determine the efficacy of the different cell transplantation procedures. While both the cell sheet and cell intramedullary injection groups showed significant motor recovery compared to the control group, the cell sheet group showed better results. Furthermore, the cell sheet group displayed a significant sensory recovery compared to the other groups. A histological evaluation revealed that the cell sheet group showed smaller injury lesion volume, less inflammation, and gliosis compared to other groups. Sensory-related fibers of μ-opioid receptors (MOR, interneuron) and hydroxytryptamine transporters (HTT, descending pain inhibitory pathway), located around the dorsal horn of the spinal cord at the caudal side of the SCI, were preserved only in the cell sheet group. Stem cells could also be found inside the peri-injured spinal cord in the cell sheet group. BMSC cell sheets were able to promote functional recovery and palliate neuropathic pain more effectively than intramedullary injections, thus serving as a good treatment option for SCI.

Sexually dimorphic response of colorectal motility to noxious stimuli in the colorectum in rats.

This study showed a remarkable sex difference in responses of colorectal motility to noxious stimuli in the colorectum in rats: colorectal motility was enhanced in response to intracolonic administration of a noxious stimulant, capsaicin, in male rats but not in female rats. The difference in descending neurons from the brain to spinal cord operating after noxious stimulation could be responsible for the sex difference. In male rats, serotoninergic and dopaminergic neurons are dominantly activated, both of which activate the spinal defaecation centre. In female rats, GABAergic neurons in addition to serotoninergic neurons are activated. GABA may compete for facilitative action of 5-HT in the spinal defaecation centre, and thereby colorectal motility is not enhanced in response to intracolonic administration of capsaicin. The findings provide a novel insight into pathophysiological mechanisms of sex differences in functional defaecation disorders such as irritable bowel syndrome. We previously demonstrated that noxious stimuli in the colorectum enhance colorectal motility through activation of descending pain inhibitory pathways in male rats. It can be expected that the regulatory mechanisms of colorectal motility differ in males and females owing to remarkable sex differences in descending pain inhibitory pathways. Thus, we aimed to clarify sex differences in responses of colorectal motility to noxious stimuli in rats. Colorectal motility was measured in vivo in anaesthetized rats. Administration of a noxious stimulant, capsaicin, into the colorectal lumen enhanced colorectal motility in male rats but not in female rats. Quantitative PCR and immunohistochemistry showed that TRPV1 expression levels in the dorsal root ganglia and in the colorectal mucosa were comparable in male and female rats. When a GABAA receptor inhibitor was intrathecally administered to the L6-S1 level of the spinal cord, colorectal motility was facilitated in response to intracolonic capsaicin even in female rats. The capsaicin-induced response in the presence of the GABA blocker in female rats was inhibited by intrathecal administration of 5-HT2 and -3 receptor antagonists but not by a D2-like dopamine receptor antagonist. Our findings demonstrate that intracolonic noxious stimulation activates GABAergic and serotoninergic descending neurons in female rats, whereas serotoninergic and dopaminergic neurons are dominantly activated in male rats. Thus, the difference in the descending neurons operating after noxious stimulation would be responsible for the sexually dimorphic responses of colorectal motility. Our findings provide a novel insight into pathophysiological mechanisms of sex differences in functional defaecation disorders such as irritable bowel syndrome.

Age-Related Changes in Pain Perception Are Associated With Altered Functional Connectivity During Resting State.

Aging affects pain experience and brain functioning. However, how aging leads to changes in pain perception and brain functional connectivity has not yet been completely understood. To investigate resting-state and pain perception changes in old and young participants, this study employed region of interest (ROI) to ROI resting-state functional connectivity (rsFC) analysis of imaging data by using regions implicated in sensory and affective dimensions of pain, descending pain modulation, and the default-mode networks (DMNs). Thirty-seven older (66.86 ± 4.04 years; 16 males) and 38 younger healthy participants (20.74 ± 4.15 years; 19 males) underwent 10 min’ eyes-closed resting-state scanning. We examined the relationship between rsFC parameters with pressure pain thresholds. Older participants showed higher pain thresholds than younger. Regarding rsFC, older adults displayed increased connectivity of pain-related sensory brain regions in comparison to younger participants: increased rsFC between bilateral primary somatosensory area (SI) and anterior cingulate cortex (ACC), and between SI(L) and secondary somatosensory area (SII)-(R) and dorsolateral prefrontal cortex (PFC). Moreover, decreased connectivity in the older compared to the younger group was found among descending pain modulatory regions: between the amygdala(R) and bilateral insula(R), thalamus(R), ACC, and amygdala(L); between the amygdala(L) and insula(R) and bilateral thalamus; between ACC and bilateral insula, and between periaqueductal gray (PAG) and bilateral thalamus. Regarding the DMN, the posterior parietal cortex and lateral parietal (LP; R) were more strongly connected in the older group than in the younger group. Correlational analyses also showed that SI(L)-SII(R) rsFC was positively associated with pressure pain thresholds in older participants. In conclusion, these findings suggest a compensatory mechanism for the sensory changes that typically accompanies aging. Furthermore, older participants showed reduced functional connectivity between key nodes of the descending pain inhibitory pathway.

Assessment of conditioned pain modulation in healthy participants and patients with chronic pain: manifestations and implications for pain progression

The purpose of this review is to summarize recent findings on conditioned pain modulation (CPM) in humans with a focus on methodology, factors modulating CPM, and the potential for CPM as a clinical marker for pain progression. CPM can be evoked by combining different stimulus modalities with good reliability; sequential CPM effects are stable over time with limited carryover effects. Optimism and pain catastrophizing might influence pain inhibition. Further, studies suggest that the CPM effect can be improved by gabapentinoids, transcranial direct current stimulation to cortical structures, and exercise and that long-term opioid use might impair CPM in patients with chronic pain. Clinical evidence suggests that preoperative impaired CPM may predict more severe chronic postoperative pain. The effect of pain duration on CPM impairment has been challenged by recent studies. As CPM methodology is optimized, studies are revealing factors that can modulate descending pain inhibitory pathways. Understanding underlying mechanisms of CPM will improve the utility of CPM in a clinical setting and potentially lead to personalized treatments for chronic pain patients.

The antinociceptive effect of anterior pretectal nucleus stimulation is mediated by distinct neurotransmitter mechanisms in descending pain pathways

Electrical stimulation of the anterior pretectal nucleus (APtN) activates two descending pain inhibitory pathways. One of these pathways relays in the ipsilateral lateral paragigantocellular nucleus (LPGi), whereas the other pathway relays in the contralateral pedunculopontine tegmental nucleus (PPTg). Antinociceptive effect of APtN stimulation has been seen in various pain models in the rodents. Similarly, LPGi or PPTg stimulation results in higher pain thresholds. Descending antinociceptive pathways activated by electrical APtN stimulation have been elucidated, but the underlying neurotransmitter mechanisms involved have not been clarified yet. This study investigates the role that endogenous signaling plays in the ipsilateral LPGi or contralateral PPTg after the APtN is stimulated in the tail-flick test. First, we submitted rats to excitotoxic injection of N-methyl-d-aspartate (NMDA) into the contralateral PPTg. Then, we examined whether blockage of NMDA (AP-7), serotonergic (methysergide), or opioid (naloxone) receptors in the ipsilateral LPGi is required for APtN stimulation-evoked analgesia (SEA). Likewise, we examined the effects of antagonists of NMDA, serotonergic, or cholinergic nicotinic (mecamylamine) receptors on the contralateral PPTg in ipsilateral LPGi-lesioned rats. Our results confirmed that APtN stimulation activates two pain inhibitory pathways and showed that endogenous opioid signaling in the ipsilateral LPGi appears to be necessary for APtN SEA and for endogenous NMDA, serotoninergic, and nicotinergic signaling in the contralateral PPTg.

The effect of occipital nerve field stimulation on the descending pain pathway in patients with fibromyalgia: a water PET and EEG imaging study

BackgroundFibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory, and mood problems. Recently, occipital nerve field stimulation (ONS) has been proposed as an effective potential treatment for fibromyalgia-related pain. The aim of this study is to unravel the neural mechanism behind occipital nerve stimulation’s ability to suppress pain in fibromyalgia patients.Materials and methodsSeven patients implanted with subcutaneous electrodes in the C2 dermatoma were enrolled for a Positron Emission Tomography (PET) H215O activation study. These seven patients were selected from a cohort of 40 patients who were part of a double blind, placebo-controlled study followed by an open label follow up at six months. The H215O PET scans were taken during both the “ON” (active stimulation) and “OFF” (stimulating device turned off) conditions. Electroencephalogram (EEG) data were also recorded for the implanted fibromyalgia patients during both the “ON” and “OFF” conditions.ResultsRelative to the “OFF” condition, ONS stimulation resulted in activation in the dorsal lateral prefrontal cortex, comprising the medial pain pathway, the ventral medial prefrontal cortex, and the bilateral anterior cingulate cortex as well as parahippocampal area, the latter two of which comprise the descending pain pathway. Relative deactivation was observed in the left somatosensory cortex, constituting the lateral pain pathway as well as other sensory areas such as the visual and auditory cortex. The EEG results also showed increased activity in the descending pain pathway. The pregenual anterior cingulate cortex extending into the ventral medial prefrontal cortex displayed this increase in the theta, alpha1, alpha2, beta1, and beta2 frequency bands.ConclusionPET shows that ONS exerts its effect via activation of the descending pain inhibitory pathway and the lateral pain pathway in fibromyalgia, while EEG shows activation of those cortical areas that could be responsible for descending inhibition system recruitment.Trial RegistrationThis study is registered with ClinicalTrials.gov, number NCT00917176 (June 10, 2009).

Descending monoaminergic pathways projecting to the spinal defecation center enhance colorectal motility in rats.

The central regulating mechanisms of defecation, especially roles of the spinal defecation center, are still unclear. We have shown that monoamines including norepinephrine, dopamine, and serotonin injected into the spinal defecation center cause propulsive contractions of the colorectum. These monoamines are the main neurotransmitters of descending pain inhibitory pathways. Therefore, we hypothesized that noxious stimuli in the colorectum would activate the descending monoaminergic pathways projecting to the spinal defecation center and that subsequently released endogenous monoamine neurotransmitters would enhance colorectal motility. Colorectal motility was measured in rats anesthetized with α-chloralose and ketamine. As a noxious stimulus, capsaicin was administered into the colorectal lumen. To interrupt neuronal transmission in the spinal defecation center, antagonists of norepinephrine, dopamine, and/or serotonin receptors were injected intrathecally at the L6-S1 spinal level, where the spinal defecation center is located. Intraluminal administration of capsaicin, acting on the transient receptor potential vanilloid 1 channel, caused transient propulsive contractions. The effect of capsaicin was abolished by surgical severing of the pelvic nerves or thoracic spinal transection at the T4 level. Capsaicin-induced contractions were blocked by preinjection of D2-like dopamine receptor and 5-hydroxytryptamine subtype 2 and 3 receptor antagonists into the spinal defecation center. We demonstrated that intraluminally administered capsaicin causes propulsive colorectal motility through reflex pathways involving the spinal and supraspinal defecation centers. Our results provide evidence that descending monoaminergic neurons are activated by noxious stimulation to the colorectum, leading to facilitation of colorectal motility. NEW & NOTEWORTHY The present study demonstrates that noxious stimuli in the colorectum activates the descending monoaminergic pathways projecting to the spinal defecation center and that subsequently released endogenous monoamine neurotransmitters, serotonin and dopamine, enhance colorectal motility. Our findings provide a possible explanation of the concurrent appearance of abdominal pain and bowel disorder in irritable bowel syndrome patients. Thus the present study may provide new insights into understanding of mechanisms of colorectal dysfunction involving the central nervous system.

Responsibility of the doctor who prescribes serotonin and noradrenaline reuptake inhibitors for patients with chronic musculoskeletal pain

Duloxetine, a serotonin and noradrenaline reuptake inhibitor (SNRI), is indicated for the management of chronic musculoskeletal pain, as it helps inhibit pain signals by activating descending pain inhibitory pathways.1 Thus, duloxetine is increasingly being prescribed by many doctors who are not familiar with psychopharmacology. We conducted a questionnaire survey on Japanese physicians’ recognition of the severe side-effects of duloxetine. We surveyed 69 physicians who had prescribed duloxetine for chronic musculoskeletal pain and 52 (75.4%) responded. The main specialties of the responders were psychosomatic medicine (n = 26, 50.0%), orthopedics (n = 14, 26.9%), anesthesiology and pain (n = 6, 11.5%), and general internal medicine (n = 6, 11.5%). The average age of the 52 responders was 52.4 years. Seventeen responders reported side-effects in their patients due to duloxetine, as follows: falls (n = 12, 23.1%), hyponatremia (n = 2, 3.8%), and discontinuation syndrome (n = 3, 5.8%). Of the 52 responders, 24 (46.2%) considered falls and syncope as a side-effect, 13 (25.0%) recognized hyponatremia as a serious complication, and only 11 (21.2%) knew about discontinuation syndrome. These results suggest that many prescription doctors are unaware or ignore these side-effects of SNRI. Of the 52 responders, 26 (50.0%) considered duloxetine as an analgesic drug, and 26 (50.0%) recognized it as an SNRI. Duloxetine has some severe side-effects at the same level as other SNRI. Syncope and orthostatic hypotension can occur at any time during treatment, particularly after dose increases. SNRI, as well as selective serotonin reuptake inhibitors (SSRI), are well known to have side-effects, including the syndrome of inappropriate antidiuretic hormone secretion, which results in hyponatremia, the most commonly encountered electrolyte abnormality in clinical practice. Following the abrupt discontinuation of SNRI, discontinuation symptoms, such as dizziness, headache, irritability, insomnia, and fatigue, may occur. Moreover, the majority of patients with chronic musculoskeletal pain are elderly and tend to have a higher underlying risk for falls, such as use of multiple medications and medical comorbidities. In Japan, after the introduction of SSRI and SNRI for depression, pharmaceutical companies initiated educational campaigns. Due to these marketing practices, SSRI and SNRI sales have achieved a tremendous increase, resulting in an increase in severe side-effects.2 We can learn a great deal from this experience with the aggressive marketing of these drugs as a kind of disease mongering. Now, the same risk exists with duloxetine for chronic musculoskeletal pain. The doctor who prescribes SNRI must weigh the benefits against the side-effects. When prescribing an SNRI for chronic musculoskeletal pain, patients should be carefully monitored against side-effects. Discontinuation should be considered in patients who experience side-effects during SNRI therapy. Even then, a gradual reduction in the dose rather than abrupt cessation is recommended, whenever possible, to prevent discontinuation syndrome. The author declares no conflicts of interest.

132 The Underlying Effect of Burst Stimulation on Chronic Pain Using Multimodal Neuroimaging - EEG, fMRI and PET

Abstract INTRODUCTION Minimally invasive neuromodulation such as spinal cord stimulation (SCS) and occipital nerve stimulation (ONS) have shown to be successful for treatment of different types of pain such as chronic back or leg pain, complex regional pain syndrome (CRPS), and fibromyalgia. Recently, novel stimulation paradigm called burst stimulation was developed that suppresses pain to better extent than classical tonic stimulation. From clinical point of view, burst stimulation is very promising; however, little is known about its underlying mechanism. Hence, in this work we investigate mechanism of action for burst stimulation in different patient groups and controls using different neuroimaging multimodalities such as EEG, fMRI and PET. METHODS Control subjects and patients with chronic back or leg pain, CRPS, or fibromyalgia enrolled for study. Both controls and patients received SCS or ONS and sham, tonic, and burst stimulation in fMRI, PET, and EEG. RESULTS >EEG shows significant changes for burst stimulation compared to tonic and sham stimulation; evident by increased activity at dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (dPFC), primary somatosensory cortex, and posterior cingulate cortex (PSC) in alpha frequency band. PET further confirmed by showing increased tracer capitation for burst in dACC, pregenual anterior cingulate cortex (pgACC), parahippocampus, and fusiform gyrus. Furthermore, fMRI showed burst changes in dACC, dPFC, pgACC, cerebellum, hypothalamus, and premotor cortex. A conjunction analysis between tonic and burst stimulation demonstrated theta activity is commonly modulated in somatosensory cortex and PSC. CONCLUSION Our data suggest that burst and tonic stimulation modulate ascending lateral and descending pain inhibitory pathways. Burst stimulation adds by modulating the medial pain pathway, possibly by direct modulation of spinothalamic pathway, as suggested by animal research. Burst normalizes an imbalance between ascending pain via medial system and descending pain inhibitory activity, which could be a plausible reason it's better than to tonic stimulation.

Exogenous serotonin regulates colorectal motility via the 5-HT2 and 5-HT3 receptors in the spinal cord of rats.

We previously reported that intrathecal injection of noradrenaline or dopamine causes enhancement of colorectal motility. As these monoamines are neurotransmitters of descending pain inhibitory pathways in the spinal cord, we hypothesized that serotonin, which is one of the neurotransmitters involved in descending pain inhibition, also influences the lumbosacral defecation center. Therefore, we examined whether serotonin acting on the spinal defecation center enhances colorectal motility. Colorectal intraluminal pressure and propelled liquid volume were recorded in vivo in anesthetized rats. Intrathecal injection of serotonin into the L6-S1 spinal cord elicited periodic increases in colorectal intraluminal pressure, being associated with increases in liquid output. Pharmacological experiments revealed that the effect of serotonin is mediated by both 5-HT2 and 5-HT3 receptors. The serotonin-induced enhancement of colorectal motility was unaffected even after disconnection of the defecation center from supraspinal regions by cutting the T8 spinal cord, while transection of the parasympathetic pelvic nerves prevented the colokinetic effect of serotonin. Finally, we investigated interactions among serotonin, noradrenaline and dopamine. Simultaneous administration of sub-effective doses of these monoamine neurotransmitters into the spinal cord caused propulsive colorectal motility slightly but substantially. These results demonstrate that exogenous serotonin acts on 5-HT2 and 5-HT3 receptors in the lumbosacral defecation center and activates the parasympathetic nervous system to enhance colorectal motility in cooperation with noradrenaline and dopamine.