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Loss-of-function mutations in Na1.7 cause congenital insensitivity to pain (CIP); this voltage-gated sodium channel is therefore a key target for analgesic drug development. Utilizing a multi-modal approach, we investigated how Na1.7 mutations lead to human pain insensitivity. Skin biopsy and microneurography revealed an absence of C-fiber nociceptors in CIP patients, reflected in a reduced cortical response to capsaicin on fMRI. Epitope tagging of endogenous Na1.7 revealed the channel to be localized at the soma membrane, axon, axon terminals, and the nodes of Ranvier of induced pluripotent stem cell (iPSC) nociceptors. CIP patient-derived iPSC nociceptors exhibited an inability to properly respond to depolarizing stimuli, demonstrating that Na1.7 is a key regulator of excitability. Using this iPSC nociceptor platform, we found that some Na1.7 blockers undergoing clinical trials lack specificity. CIP, therefore, arises due to a profound loss of functional nociceptors, which is more pronounced than that reported in rodent models, or likely achievable following acute pharmacological blockade.
Learn More >Current understanding of the origin of occipital headache falls short of distinguishing between cause and effect. Most preclinical studies involving trigeminovascular neurons sample neurons that are responsive to stimulation of dural areas in the anterior 2/3 of the cranium and the periorbital skin. Hypothesizing that occipital headache may involve activation of meningeal nociceptors that innervate the posterior 1/3 of the dura, we sought to map the origin and course of meningeal nociceptors that innervate the posterior dura overlying the cerebellum. Using AAV-GFP tracing and single-unit recording techniques in male rats, we found that neurons in C2-3 DRGs innervate the dura of the posterior fossa; that nearly half originate in DRG neurons containing CGRP and TRPV1; that nerve bundles traverse suboccipital muscles before entering the cranium through bony canals and large foramens; that central neurons receiving nociceptive information from the posterior dura are located in C2-4 spinal cord and that their cutaneous and muscle receptive fields are found around the ears, occipital skin and neck muscles; and that administration of inflammatory mediators to their dural receptive field, sensitize their responses to stimulation of the posterior dura, peri-occipital skin and neck muscles. These findings lend rationale for the common practice of attempting to alleviate migraine headaches by targeting the greater and lesser occipital nerves with anesthetics. The findings also raise the possibility that such procedures may be more beneficial for alleviating occipital than non-occipital headaches and that occipital migraines may be associated more closely with cerebellar abnormalities than in non-occipital migraines.Occipital headaches are common in both migraine and non-migraine headaches. Historically, two distinct scenarios have been proposed for such headaches; the first suggests that the headaches are caused by spasm or tension of scalp, shoulders and neck muscles inserted in the occipital region whereas the second suggests that these headaches are initiated by activation of meningeal nociceptors. The current study shows that the posterior dura overlying the cerebellum is innervated by cervicovascular neurons in C2 DRG whose axons reach the posterior dura through multiple intra- and extra-cranial pathways, and sensitization of central cervicovascular neurons from the posterior dura can result in hyperresponsiveness to stimulation of neck muscles. The findings suggest that the origin of occipital and frontal migraine may differ.
Learn More >Low back pain is associated with degeneration of the intervertebral disc, but specific mechanisms of pain generation in this pathology remain unknown. Sensory afferent nerve fiber growth into the intervertebral disc after injury-induced inflammation may contribute to discogenic pain. We describe a clinically relevant behavioral phenotype in a rodent model of chronic intervertebral disc degeneration which provides a means to map sensory neuron changes to a single affected lumbar intervertebral disc. Unilateral disc puncture of one lumbar intervertebral disc revealed a bilateral behavioral phenotype characterized by gait changes and decreased activity. Moreover, neurons extracted from the dorsal root ganglia in animals with intervertebral disc injury demonstrated altered TRPV1 activation in vitro independent of exogenous NGF administration. Finally, neuronal nuclear hypertrophy and elevated expression of p75NTR provide evidence of active adaptation of innervating sensory neurons in chronic intervertebral disc degeneration. Therefore, this model and findings provide the template for future studies to establish specific mechanisms of nociceptive pain in chronic intervertebral disc degeneration.
Learn More >The transient receptor potential ankyrin A 1 (TRPA1) channel and calcitonin gene-related peptide (CGRP) are targets for migraine prophylaxis. This study aimed to understand their mechanisms in migraine by investigating the role of TRPA1 in cortical spreading depression (CSD) in vivo and exploring how reactive oxygen species (ROS)/TRPA1/CGRP interplay in regulating cortical susceptibility to CSD.
Learn More >Pain is a subjective sensory experience that can, mostly, be reported but cannot be directly measured or quantified. Nevertheless, a suite of biomarkers related to mechanisms, neural activity, and susceptibility offer the possibility-especially when used in combination-to produce objective pain-related indicators with the specificity and sensitivity required for diagnosis and for evaluation of risk of developing pain and of analgesic efficacy. Such composite biomarkers will also provide improved understanding of pain pathophysiology.
Learn More >Chronic musculoskeletal pain affects a substantial portion of adults visiting the emergency department (ED). Current treatment is limited in scope and does not effectively reduce musculoskeletal pain in patients. The study will evaluate the use of duloxetine, a serotonin-norepinephrine reuptake inhibitor Food and Drug Administration approved for the treatment of chronic pain, as a promising option in its prevention. The proposed study may present a well-tolerated and effective non-opioid treatment for patients with acute musculoskeletal pain that may also be effective in preventing the transition to persistent or chronic musculoskeletal pain.
Learn More >It has been known for decades that classical conditioning influences pain perception. However, the precise relationship between conditioning and pain remains unclear. In addition, the clinical implications of their relationship are vastly underappreciated. Thus, we aim to (a) examine how conditioning increases or decreases pain sensitivity, (b) assess how conditioning contributes to the development and maintenance of chronic pain, and (c) explore strategies to utilize conditioning to optimize pain treatment.
Learn More >The use of compounded topical pain creams has increased dramatically, yet their effectiveness has not been well evaluated.
Learn More >To study iron deposition in red nucleus (RN), globus pallidus (GP), and periaqueductal gray matter (PAG) as a potential biomarker of chronic migraine (CM) and its association with levels of biomarkers related to migraine pathophysiology.
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