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Aerobic exercise is believed to be an effective chronic low back pain (CLBP) intervention, although its mechanisms remain largely untested. This study evaluated whether endogenous opioid (EO) mechanisms contributed to the analgesic effects of an aerobic exercise intervention for CLBP. Individuals with CLBP were randomized to a 6-week, 18-session aerobic exercise intervention (n = 38) or usual activity control (n = 44). Before and after the intervention, participants underwent separate laboratory sessions to assess responses to evoked heat pain after receiving saline placebo or i.v. naloxone (opioid antagonist) in double-blinded, crossover fashion. Chronic pain intensity and interference were assessed before and after the intervention. EO analgesia was indexed by naloxone-placebo condition differences in evoked pain responses (blockade effects). Relative to controls, exercise participants reported significantly greater pre-post intervention decreases in chronic pain intensity and interference (p's < .04) and larger reductions in placebo condition evoked pain responsiveness (McGill Pain Questionnaire-Short Form [MPQ]-Total). At the group level, EO analgesia (MPQ-Total blockade effects) increased significantly pre-post intervention only among female exercisers (p = .03). Dose-response effects were suggested by a significant positive association in the exercise group between exercise intensity (based on meeting heart rate targets) and EO increases (MPQ-Present Pain Intensity; p = .04). Enhanced EO analgesia (MPQ-Total) was associated with significantly greater improvement in average chronic pain intensity (p = .009). Aerobic exercise training in the absence of other interventions appears effective for CLBP management. Aerobic exercise-related enhancements in endogenous pain inhibition, in part EO-related, likely contribute to these benefits.
Learn More >Migraine is a complex and disabling neurological disorder, and the exact neurological mechanisms remain unclear. Thalamus is considered the hub of the central processing and integration of nociceptive information, as well as the modulation of these processes.
Learn More >While dipyrone is a widely used analgesic, its mechanism of action is not completely understood. Recently we have reported that the dipyrone metabolite 4-aminoantipirine (4-AA) reduces prostaglandin E (PGE )-induced pain-related behaviour through the cannabinoid type 1 (CB1) receptor. Here, we ascertained, in naive and PGE -induced "inflamed" conditions, both in vivo and in vitro, the molecular mechanisms involved in the 4-AA-induced analgesic effects.
Learn More >The COVID-19 health emergency has led many Headache providers to transition to virtual care overnight without preparation. We review our experience and discuss tips to bring humanity to the virtual visits.
Learn More >Nonsteroidal anti-inflammatory drugs (NSAIDs) are, in general, the cornerstone of musculoskeletal pain management; however, systemic adverse events with oral formulations of NSAIDs are common. To address this problem and limit systemic exposure, topical formulations of some NSAIDs have been developed. The aim of this systematic review was to assess the available evidence on the efficacy and safety of the topical formulations of the NSAID etofenamate in patients with musculoskeletal disorders.
Learn More >PIEZO2 is the essential transduction channel for touch discrimination, vibration, and proprioception. Mice and humans lacking Piezo2 experience severe mechanosensory and proprioceptive deficits and fail to develop tactile allodynia. Bradykinin, a proalgesic agent released during inflammation, potentiates PIEZO2 activity. Molecules that decrease PIEZO2 function could reduce heightened touch responses during inflammation. Here, we find that the dietary fatty acid margaric acid (MA) decreases PIEZO2 function in a dose-dependent manner. Chimera analyses demonstrate that the PIEZO2 beam is a key region tuning MA-mediated channel inhibition. MA reduces neuronal action potential firing elicited by mechanical stimuli in mice and rat neurons and counteracts PIEZO2 sensitization by bradykinin. Finally, we demonstrate that this saturated fatty acid decreases PIEZO2 currents in touch neurons derived from human induced pluripotent stem cells. Our findings report on a natural product that inhibits PIEZO2 function and counteracts neuronal mechanical sensitization and reveal a key region for channel inhibition.
Learn More >Activation of kappa opioid receptor (KOR) produces analgesia, antipruritic effect, sedation and dysphoria. To characterize neuroanatomy of KOR at high resolutions and circumvent issues of specificity of KOR antibodies, we generated a knock-in mouse line expressing KOR fused at the C-terminus with the fluorescent protein tdTomato (KtdT). The selective KOR agonist U50,488H caused anti-scratch effect and hypolocomotion, indicating intact KOR neuronal circuitries. Clearing of brains with CLARITY revealed 3-dimensional (3-D) images of distribution of KOR, and any G protein-coupled receptors, for the first time. 3-D brain images of KtdT and immunohistochemistry (IHC) on brain sections with antibodies against tdTomato show similar distribution to that of autoradiography of [H]U69,593 binding to KOR in wildtype mice. KtdT was observed in regions involved in reward and aversion, pain modulation and neuroendocrine regulation. KOR is present in several areas with unknown roles, including the claustrum, dorsal endopiriform nucleus, paraventricular nucleus of the thalamus, lateral habenula and substantia nigra pars reticulata (SNr), which are discussed. Prominent KtdT-containing fibers were observed to project from caudate putamen (CP) and nucleus accumbens (ACB) to substantia innominata (SI) and SNr. Double IHC revealed co-localization of KtdT with tyrosine hydroxylase (TH) in brain regions, including CP, ACB and ventral tegmental area (VTA). KOR was visualized at the cellular level, such as co-localization with TH and agonist-induced KOR translocation into intracellular space in some VTA neurons. These mice thus represent a powerful and heretofore unparalleled tool for neuroanatomy of KOR at both the 3-D and cellular levels. A combination of tagging KOR with tdTomato and tissue clearing with CLARITY enables 3-D mouse brain imaging of KOR, or any G protein-coupled receptors, for the first time. This approach reveals prominent KOR-expressing fiber bundles from caudate putamen and nucleus accumbens to substantia nigra pars reticulata and allows visualization of the KOR at the cellular level, including co-localization with TH and agonist-induced KOR translocation in some neurons. Regions expressing moderate to high KOR, but with no known functions, are highlighted and discussed, including claustrum, dorsal endopiriform nucleus, paraventricular nucleus of the thalamus and lateral habenula. The mouse line will be a valuable tool for investigation of KOR neurobiology. This approach paves ways for future similar studies.
Learn More >An increasing number of patients with chronic persistent post-traumatic headache (PPTH) after mild traumatic brain injury (MTBI) are being referred to headache or pain specialists as conventional treatment options for primary headache disorders have not been able to adequately alleviate their debilitating headache symptoms. Evolving clinical and mechanistic evidences support the notation that chronic persistent MTBI related headaches (MTBI-HA) carry the hallmark characteristics of neuropathic pain. Thus, in addition to conventional treatment options applicable to non-traumatic primary headache disorders, other available treatment modalities for neuropathic pain should be considered. In this comprehensive review article, the author reveals the prevalence of MTBI-HA and its clinical manifestation, discusses existing clinical and mechanistic evidence supporting the classification of chronic persistent MTBI-HA as a neuropathic pain state, and explores current available treatment options and future directions of therapeutic research related to MTBI-HA.
Learn More >Chronic pain surrounding the temporomandibular joints and masticatory muscles is often the primary chief complaint of patients with temporomandibular disorders (TMD) seeking treatment. Yet, the neuro-pathophysiological basis underlying it remains to be clarified. Neuroimaging techniques have provided a deeper understanding of what happens to brain structure and function in TMD patients with chronic pain. Therefore, we performed a systematic review of magnetic resonance imaging (MRI) studies investigating structural and functional brain alterations in TMD patients to further unravel the neurobiological underpinnings of TMD-related pain. Online databases (PubMed, EMBASE, and Web of Science) were searched up to August 3, 2019, as complemented by a hand search in reference lists. A total of 622 papers were initially identified after duplicates removed and 25 studies met inclusion criteria for this review. Notably, the variations of MRI techniques used and study design among included studies preclude a meta-analysis and we discussed the findings qualitatively according to the specific neural system or network the brain regions were involved in. Brain changes were found in pathways responsible for abnormal pain perception, including the classic trigemino-thalamo-cortical system and the lateral and medial pain systems. Dysfunction and maladaptive changes were also identified in the default mode network, the top-down antinociceptive periaqueductal gray-raphe magnus pathway, as well as the motor system. TMD patients displayed altered brain activations in response to both innocuous and painful stimuli compared with healthy controls. Additionally, evidence indicates that splint therapy can alleviate TMD-related symptoms by inducing functional brain changes. In summary, MRI research provides important novel insights into the altered neural manifestations underlying chronic pain in TMD.
Learn More >Painful traumatic trigeminal neuropathy (PTTN) may occur following major craniofacial or oral trauma, or may be subsequent to relatively minor dental interventions. Following injury, pain may originate from a peripheral nerve, a ganglion, or from the central nervous system. In this review, we focus on molecular mechanisms of pain resulting from injury to the peripheral branch of the trigeminal nerve. This syndrome has been termed painful traumatic trigeminal neuropathy (PTTN) by the International Headache Society and replaces previous terms including atypical odontalgia, deafferentation pain, traumatic neuropathy and phantom toothache. We emphasize the scientific evidence supporting the events purported to lead to PTTN by reviewing the pathophysiology of PTTN based on relevant animal models. Additionally, we briefly overview clinical correlates and pathophysiological manifestations of PTTN.
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