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Interactions between epithelial cells and neurons influence a range of sensory modalities including taste, touch, and smell. Vertebrate and invertebrate epidermal cells ensheath peripheral arbors of somatosensory neurons, including nociceptors, yet the developmental origins and functional roles of this ensheathment are largely unknown. Here, we describe an evolutionarily conserved morphogenetic mechanism for epidermal ensheathment of somatosensory neurites. We found that somatosensory neurons in and zebrafish induce formation of epidermal sheaths, which wrap neurites of different types of neurons to different extents. Neurites induce formation of plasma membrane phosphatidylinositol 4,5-bisphosphate microdomains at nascent sheaths, followed by a filamentous actin network, and recruitment of junctional proteins that likely form autotypic junctions to seal sheaths. Finally, blocking epidermal sheath formation destabilized dendrite branches and reduced nociceptive sensitivity in . Epidermal somatosensory neurite ensheathment is thus a deeply conserved cellular process that contributes to the morphogenesis and function of nociceptive sensory neurons.
Learn More >Low back pain encompasses three distinct sources: axial lumbosacral, radicular, and referred pain. Annually, the prevalence of low back pain in the general US adult population is 10-30%, and the lifetime prevalence of US adults is as high as 65-80%.
Learn More >An increasing amount of literature supports a multimodal approach to analgesic administration in the management of postoperative pain. The purpose of this study and review was to further evaluate the differences in efficacy in controlling immediate postoperative pain among the various routes of analgesia administration.
Learn More >Worldwide, women account for approximately 51% of human immunodeficiency virus-1 (HIV) seropositive individuals. The prevalence of neuropathic pain among individuals with HIV and a lack of preclinical data characterizing sex differences prompted us to address this knowledge gap. C57BL/6 male and female mice received multiple intrathecal injections of HIV-glycoprotein 120 (gp120), followed by determination of mechanical allodynia and thermal hypersensitivity for four weeks. The influence of ovarian hormones in the gp120 pain model was evaluated by comparison of ovariectomized (OVX) mice versus sham control. We found that gp120-induced neuropathic pain-like behaviors are sex-dependent. Female mice showed both increased mechanical allodynia and increased cold sensitivity relative to their male counterparts. The OVX mice showed reduced pain sensitivity compared to sham, suggesting a role of the ovarian hormones in sex differences in pain sensitivity to gp120. Gp120-induced neuropathic pain caused a shift in estrous cycle toward the estrus phase. However, there is a lack of clear correlation between the estrous cycle and the development of neuropathic pain-like behaviors during the four week recording period. This data provided the first evidence for sex differences in a rodent model of HIV-related neuropathic pain, along with a potential role of ovarian hormones.
Learn More >Peripheral inflammation produces a long-lasting latent sensitization of spinal nociceptive neurons that is masked by tonic inhibitory controls. We explored mechanisms of latent sensitization with an established four-step approach: 1) induction of inflammation; 2) allow pain hypersensitivity to resolve; 3) interrogate latent sensitization with a channel blocker, mutant mouse, or receptor antagonist; 4) disrupt compensatory inhibition with a receptor antagonist so as to reinstate pain hypersensitivity. We found that the neuropeptide Y Y1 receptor antagonist BIBO3304 reinstated pain hypersensitivity, indicative of an unmasking of latent sensitization. BIBO3304-evoked reinstatement was not observed in AC1 knockout mice and was prevented with intrathecal co-administration of a pharmacological blocker to either: the N-methyl-D-aspartate receptor (NMDAR); adenylyl cyclase type 1 (AC1); protein kinase A (PKA); transient receptor potential cation channel A1 (TRPA1); channel V1 (TRPV1); or exchange protein activated by cAMP (Epac1 or Epac2). A PKA activator evoked both pain reinstatement and touch-evoked pERK expression in dorsal horn; the former was prevented with intrathecal co-administration of a TRPA1 or TRPV1 blocker. An Epac activator also evoked pain reinstatement and pERK expression. We conclude that PKA and Epac are sufficient to maintain long-lasting latent sensitization of dorsal horn neurons that is kept in remission by the NPY-Y1 receptor system. Furthermore, we have identified and characterized two novel molecular signaling pathways in the dorsal horn that drive latent sensitization in the setting of chronic inflammatory pain: NMDAR→AC1→PKA→TRPA1/V1 and NMDAR→AC1→Epac1/2. New treatments for chronic inflammatory pain might either increase endogenous NPY analgesia or inhibit AC1, PKA or Epac.
Learn More >To investigate associations between a range of different indicators of socioeconomic position (SEP: occupational class, education, household overcrowding and tenure, and experience of financial hardship) across life and chronic widespread and regional pain (CWP and CRP) at age 68.
Learn More >The PREEMPT Studies established onabotulinumtoxinA as preventive treatment for adults with chronic migraine (CM). The purpose of the REal-life use of botulinum toxin for the symptomatic treatment of adults with chronic migraine, measuring healthcare resource utilisation, and Patient-reported OutcomeS observed in practice (REPOSE) Study was to observe real-life, long-term (24-month) use of onabotulinumtoxinA in adults with CM and report on the utilisation, effectiveness, safety, and tolerability.
Learn More >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.
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