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Unique features of sensory neuron subtypes are manifest by their distinct physiological and pathophysiological functions. Using patch-clamp electrophysiology, Ca imaging, calcitonin gene-related peptide release assay from tissues, protein biochemistry approaches, and behavioral physiology on pain models, this study demonstrates the diversity of sensory neuron pathophysiology is due in part to subtype-dependent sensitization of TRPV1 and TRPA1. Differential sensitization is influenced by distinct expression of inflammatory mediators, such as prostaglandin E (PGE), bradykinin (BK), and nerve growth factor (NGF) as well as multiple kinases, including protein kinase A (PKA) and C (PKC). However, the co-expression and interaction of TRPA1 with TRPV1 proved to be the most critical for differential sensitization of sensory neurons. We identified N- and C-terminal domains on TRPV1 responsible for TRPA1-TRPV1 (A1-V1) complex formation. Ablation of A1-V1 complex with dominant-negative peptides against these domains substantially reduced the sensitization of TRPA1, as well as BK- and CFA-induced hypersensitivity. These data indicate that often occurring TRP channel complexes regulate diversity in neuronal sensitization and may provide a therapeutic target for many neuroinflammatory pain conditions.
Learn More >The mature peripheral nervous system is a steady network structure yet shows remarkable regenerative properties. The interaction of peripheral nerves with myeloid cells has largely been investigated in the context of damage, following trauma or infection. Recently, specific macrophages dedicated to homeostatic peripheral nerves have come into focus. These macrophages are defined by tissue and nerve type, are seeded in part prenatally, and self-maintain via proliferation. Thus, they are markedly distinct from monocyte-derived macrophages invading after local disturbance of nerve integrity. The phenotypic and transcriptional adaptation of macrophages to the discrete nervous niche may exert axon guidance and nerve regeneration and thus contribute to the stability of the peripheral nervous network. Deciphering these conserved macrophage-nerve interactions offers new translational perspectives for chronic diseases of the peripheral nervous system, such as diabetic neuropathy and pain.
Learn More >To assess the effects of pharmacological therapies for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) PATIENTS AND METHODS: We performed a comprehensive search using multiple databases, trial registries, grey literature and conference proceedings with no restrictions on the language of publication or publication status. The date of the latest search of all databases was July 2019. We included randomised controlled trials. Inclusion criteria were men with a diagnosis of CP/CPPS. We included all available pharmacological interventions. Two review authors independently classified studies and abstracted data from the included studies, performed statistical analyses and rated quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. The primary outcomes were prostatitis symptoms and adverse events. The secondary outcomes were sexual dysfunction, urinary symptoms, quality of life, anxiety and depression.
Learn More >Chronic pain following spinal cord injury (SCI) is associated with electrical hyperactivity (spontaneous and evoked) in primary nociceptors. Cyclic adenosine monophosphate (cAMP) signaling is an important contributor to nociceptor excitability, and knockdown of the cAMP effector, exchange protein activated by cAMP (EPAC), has been shown to relieve pain-like responses in several chronic pain models. To examine potentially distinct roles of each EPAC isoform (EPAC1 and 2) in maintaining chronic pain, we used rat and mouse models of contusive spinal cord injury (SCI). Pharmacological inhibition of EPAC1 or 2 in a rat SCI model was sufficient to reverse SCI-induced nociceptor hyperactivity, indicating that EPAC1 and 2 signaling activity are complementary, with both required to maintain hyperactivity. However, EPAC activation was not sufficient to induce similar hyperactivity in nociceptors from naïve rats, and we observed no change in EPAC protein expression after SCI. In the mouse SCI model, inhibition of both EPAC isoforms through a combination of pharmacological inhibition and genetic deletion was required to reverse SCI-induced nociceptor hyperactivity. This was consistent with our finding that neither EPAC1 nor EPAC2 mice were protected against SCI-induced chronic pain as assessed with an operant mechanical conflict test. Thus, EPAC1 and 2 activity may play a redundant role in mouse nociceptors, although no corresponding change in EPAC protein expression levels was detected after SCI. Despite some differences between these species, our data demonstrate a fundamental role for both EPAC1 and EPAC2 in mechanisms maintaining nociceptor hyperactivity and chronic pain after SCI.
Learn More >Both inhibiting ascending nociceptive transmission and activating descending inhibition are involved in the opioid analgesic effect. The spinal dorsal horn is a critical site for modulating nociceptive transmission by descending pathways elicited by opioids in the brain. μ-Opioid receptors (MORs, encoded by Oprm1) are highly expressed in primary sensory neurons and their central terminals in the spinal cord. In the present study, we tested the hypothesis that MORs expressed in primary sensory neurons contribute to the descending inhibition and supraspinal analgesic effect induced by centrally administered opioids. We generated Oprm1 conditional knockout (Oprm1-cKO) mice by crossing Advillin mice with Oprm1 mice. Immunocytochemcal labeling in Oprm1-cKO mice showed that MORs are completely ablated from primary sensory neurons and are profoundly reduced in the superficial spinal dorsal horn. Intracerebroventricular injection of morphine or fentanyl produced a potent analgesic effect in wild-type mice, but such an effect was significantly attenuated in Oprm1-cKO mice. Furthermore, the analgesic effect produced by morphine or fentanyl microinjected into the periaqueductal gray was significantly greater in wild-type mice than in Oprm1-cKO mice. Blocking MORs at the spinal cord level diminished the analgesic effect of morphine and fentanyl microinjected into the periaqueductal gray in both groups of mice. Our findings indicate that MORs expressed at primary afferent terminals in the spinal cord contribute to the supraspinal opioid analgesic effect. These presynaptic MORs in the spinal cord may serve as an interface between ascending inhibition and descending modulation that are involved in opioid analgesia.
Learn More >To examine the cardiovascular, cerebrovascular, and peripheral vascular safety of erenumab across migraine prevention studies.
Learn More >The purpose of the study was to explore clinical management for new cases of musculoskeletal pain that are likely chronic. We used data from the National Ambulatory Medical Care Survey, 2007-2015, identifying visits with a new chronic musculoskeletal pain condition using pre-determined ICD-9 codes. We documented prescribing of non-opioid pain medication, opioids, physical therapy (PT), counseling, and other nonpharmacologic treatments and explored associations between patient and provider factors for each of these treatments. There were 111,994 visits over the 9-year period for a new case of chronic musculoskeletal pain, representing an average of 36.8 million weighted visits per year or approximately 11.8% of the population. Proportions that were prescribed nonopioid medication, opioids, PT, counseling and other nonpharmacologic treatments were: 40.2, 21.5, 10.0, 15.2 and 14.3 respectively. Patient age was associated with type of treatment with a young to old gradient for other nonpharmacologic treatments, PT, opioids, counseling and other medications. Orthopedists were less likely to prescribe pharmacological treatments than family practice physicians and more likely to prescribe PT. Physicians who used the electronic medical record were more likely to prescribe opioids. Contrary to practice guidelines for managing musculoskeletal pain, many patients are prescribed opioids for a new chronic musculoskeletal problem. PERSPECTIVE: We outlined in a representative sample of Americans what treatments are being prescribed for new cases of likely chronic musculoskeletal pain. Opioid prescription was double that of physical therapy. Using the electronic medical record was associated with more opioid prescription- a novel finding that should be corroborated by future research.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment, resulting in pain, numbness, instability, and thus affecting quality of life (QoL), occasionally leading to discontinuation of chemotherapy. Pharmacological treatments are not sufficient. Non-pharmacological interventions (NPIs) have also been tried. This study aimed to systematically review the efficacy of NPIs on pain and QoL in patients suffering from CIPN.
Learn More >Unlike conventional dorsal spinal cord stimulation (SCS)-which uses single pulses at a fixed rate-burst SCS uses a fixed-rate, five-pulse stimuli cluster as a treatment for chronic pain; mechanistic explanations suggest burst SCS differentially modulate the medial and lateral pain pathways vs conventional SCS. Neural activation differences between burst and conventional SCS are quantifiable with the spinal-evoked compound action potential (ECAP), an electrical measure of synchronous neural activation.
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