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Seasonal rhythms influence emotion and sociability. The brain μ-opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains elusive with no previously reported evidence. Here, we first conducted a cross-sectional study with previously acquired human [C]carfentanil PET imaging data (132 male and 72 female healthy subjects) to test whether there was seasonal difference in MOR availability. We then investigated experimentally whether seasonal variation in daylength causally influences brain MOR availability in rats. Rats (six male and three female rats) underwent daylength cycle simulating seasonal changes; control animals (two male and one female rats) were kept under constant daylength. Animals were scanned repeatedly with [C]carfentanil PET imaging. Seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability in humans. Brain regions sensitive to daylength spanned the socio-emotional brain circuits, where MOR availability formed a spring-like peak. In rats, MOR availabilities in the brain neocortex, thalamus and striatum peaked at intermediate daylength. Varying daylength also affected the weight gain and stress hormone. We conclude that the brain MOR availability in humans and rats shows significant seasonal variation, which is predominately associated with seasonal photoperiodic variation. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.Seasonal rhythms influence emotion and sociability. The brain's μ-opioid receptor (MOR) system modulates numerous seasonally varying socioemotional functions, but its seasonal variation remains elusive. Here we used positron emission tomography to show that MOR levels in both human and rat brains show daylength-dependent seasonal variation. The highest MOR availability was observed at intermediate daylengths. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.
Learn More >To characterize the distribution and severity of sensory neuropathy using a portable quantitative sensory testing (QST) device in diabetic patients (DM) hospitalized with severe COVID-19 infection.
Learn More >Of painful conditions, somatic pain of acute nociceptive origin can be effectively managed clinically, while neuropathic pain of chronic neuropathy origin is difficult to control. For molecules involved in pain sensation, substance P (SP) is algesic, exacerbating painful sensation, while its amino-terminal fragment, heptapeptide SP, confers biological activities different from its full-length parent neuropeptide precursor. We previously demonstrated SP interaction with pain processing to alleviate chronic pain. Here we evaluated SP and its C-terminal amidated analogue SPamide, together with SP and opioid agonist DAMGO. We tested mouse behaviors of both acute somatic pain in tail-flick latency assay, and neuropathic pain in sciatic nerve injury model of chronic constriction injury (CCI). DAMGO produced dose-dependent analgesia for somatic pain as expected, so did both SP and its analogue SPamide, while SP yielded the opposite effect of algesia, in a phenomenon we termed 'contrintus', meaning 'opposite from within' to denote that two peptides of the same origin (SP and its metabolic fragment SP) produced opposite effects. In CCI model, DAMGO showed a general reduction in allodynia sensitivity for both nerve-injured and normal paws, without selective effect for neuropathic pain, consistent with clinical observation that opioids are less effective for chronic neuropathic pain. On the other hand, both SP and SPamide displayed dose-dependent anti-allodynia effect that is selective for neuropathic pain. These findings suggest that SP and its analogue may be useful for developing pharmaceuticals to treat neuropathic pain.
Learn More >The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPγS binding over βarrestin2 recruitment in cellular assays, thereby demonstrating signaling bias. In mice, SR-17018 stimulates GTPγS binding in brainstem and produces antinociception with potencies similar to morphine. However, it produces much less respiratory suppression and mice do not develop antinociceptive tolerance in the hot plate assay upon repeated dosing. Herein we evaluate the effects of acute and repeated dosing of SR-17018, oxycodone and morphine in additional models of pain-related behaviors. In the mouse warm water tail immersion assay, an assessment of spinal reflex to thermal nociception, repeated administration of SR-17018 produces tolerance as does morphine and oxycodone. SR-17018 retains efficacy in a formalin-induced inflammatory pain model upon repeated dosing, while oxycodone does not. In a chemotherapeutic-induced neuropathy pain model SR-17018 is more potent and efficacious than morphine or oxycodone, moreover, this efficacy is retained upon repeated dosing of SR-17018. These findings demonstrate that, with the exception of the tail flick test, SR-17018 retains efficacy upon chronic treatment across several pain models.
Learn More >Pain is a common symptom in endodontic conditions, but differential diagnostic procedures are often needed to exclude other pain origins. General dentists and endodontists thus need to be aware of alternative painful orofacial conditions, and be able to identify them. The new International Classification of Orofacial Pain (ICOP, 2020) is the first comprehensive classification that uniquely deals with orofacial pain. The ICOP is a hierarchical classification, modelled on the International Classification of Headache Disorders (ICHD-3) and covers pain in dentoalveolar and anatomically related tissues, muscle pain, temporomandibular joint (TMJ) pain, neuropathic pain affecting cranial nerves, pain resembling primary headaches, and idiopathic pain in the orofacial region. A description of each condition is given, and structured diagnostic criteria for each condition are proposed based on research data when available. This narrative review aims to (i) give an overview and brief explanation of the ICOP system, (ii) describe and give examples of how it can be of use to general dentists and endodontists with special attention to differential diagnosis of tooth pain, and (iii) highlight how endodontic research can contribute to validation and improvement of the classification. A comparison to other classification and diagnostic systems is also included.
Learn More >No studies have prospectively investigated headache at onset of first-ever ischemic stroke, along with a large concurrent control group. Our aims were to answer two important questions: 1) are headaches at stroke onset causally related to the stroke and what are their typical clinical characteristics? 2) what aetiology of stroke is associated with these headaches?
Learn More >A serious adverse effect of prescription opioid analgesics is addiction, both to these analgesics and to illicit drugs like heroin that also activate the µ-opioid receptor (MOR). Opioid use disorder (OUD) and opioid overdose deaths represent a current American health crisis, and the prescription of opioid analgesics has contributed significantly to this crisis. While prescription opioids are highly effective analgesics, there currently exists no facile way to use them for extended periods without the risk of addiction. If addiction caused by MOR-targeting analgesics could be blocked by blending in a new "antiaddiction" ingredient that does not diminish analgesia and does not introduce its own therapeutically limiting side effects, then continued clinical use of prescription opioids for treating pain could be maintained (or even enhanced) instead of curtailed. In this narrative review, we contextualize this hypothesis, first with a brief overview of the current American opioid addiction crisis. The neurobiology of 2 key receptors in OUD development, MOR and the κ-opioid receptor (KOR), is then discussed to highlight the neuroanatomical features and circuitry in which signal transduction from these receptors lie in opposition-creating opportunities for pharmacological intervention in curtailing the addictive potential of MOR agonism. Prior findings with mixed MOR/KOR agonists are considered before exploring new potential avenues such as biased KOR agonists. New preclinical data are highlighted, demonstrating that the G protein-biased KOR agonist nalfurafine reduces the rewarding properties of MOR-targeting analgesics and enhances MOR-targeting analgesic-induced antinociception. Finally, we discuss the recent discovery that a regulator of G protein signaling (namely, RGS12) is a key component of signaling bias at KOR, presenting another drug discovery target toward identifying a single agent or adjuvant to be added to traditional opioid analgesics that could reduce or eliminate the addictive potential of the latter drug.
Learn More >Chronic pelvic pain persists in some women with endometriosis even after lesion removal and optimized hormonal treatment.
Learn More >Dependence-like behaviour may complicate withdrawal and increase risk of relapse of medication overuse headache (MOH). The most effective treatment for reducing dependence-like behaviour is unknown.
Learn More >We sought to assess factors associated with the frequency of self-reported prescription opioid use in persons with migraine, including demographic variables, comorbidities, headache characteristics, and patterns of consultation.
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