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Activation of TRPV4 on dural afferents produces headache-related behavior in a preclinical rat model.

ABSTRACT: The mechanisms contributing to the pain of migraine are poorly understood although activation of afferent nociceptors in the trigeminovascular system has been proposed as a key event. Prior studies have shown that dural-afferent nociceptors are sensitive to both osmotic and mechanical stimuli. Based on the sensitivity to these stimuli we hypothesized that dural afferents express the osmo/mechano-sensitive channel transient receptor-potential vanilloid 4 (TRPV4).These studies used in vitro patch-clamp electrophysiology of trigeminal neurons retrogradely labeled from the dura to examine the functional expression of TRPV4. Additionally, we used a rat headache model in which facial/hind paw allodynia following dural stimulation is measured to determine whether activation of meningeal TRPV4 produces responses consistent with migraine.These studies found that 56% and 49% of identified dural afferents generate currents in response to hypotonic solutions and 4?-PDD, respectively. The response to these stimuli indicates that dural afferents express TRPV4. Activation of meningeal TPRV4 using hypotonic solution or 4?-PDD in vivo resulted in both facial and hind paw allodynia that was blocked by the TRPV4 antagonist RN1734.These data indicate that activation of TRPV4 within the meninges produces afferent nociceptive signaling from the head that may contribute to migraine headache.

SUBMITTER: Wei X

PROVIDER: S-EPMC3543146 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Activation of TRPV4 on dural afferents produces headache-related behavior in a preclinical rat model.

Wei Xiaomei X Edelmayer Rebecca M RM Yan Jin J Dussor Gregory G

Cephalalgia : an international journal of headache 20111102 16

<h4>Background</h4>The mechanisms contributing to the pain of migraine are poorly understood although activation of afferent nociceptors in the trigeminovascular system has been proposed as a key event. Prior studies have shown that dural-afferent nociceptors are sensitive to both osmotic and mechanical stimuli. Based on the sensitivity to these stimuli we hypothesized that dural afferents express the osmo/mechano-sensitive channel transient receptor-potential vanilloid 4 (TRPV4).<h4>Methods</h4 ...[more]

PMID: 22049072

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Project description:BACKGROUND:Dural arteriovenous fistulas are intracranial vascular malformations, fed by dural arteries and draining venous sinuses or meningeal veins. Clinical course varies widely and ranges from benign with spontaneous remission to fatal, due to cerebral hemorrhage. In a 10-year single institution experience, clinical presentation of dural arteriovenous fistulas, and in particular headache and angiographic features, as well as long-term outcome were analyzed. METHODS:Data of 42 intracranial dural arteriovenous fistulas of 40 patients concerning demographic characteristics, medical history and risk factors, clinical presentation and headache features, location and neuroimaging findings, as well as treatment and outcome, were collected. Furthermore, we used the modified-Rankin Scale to assess the long-term outcome, by telephone contact with patients and/or their relatives. RESULTS:Patients aged between 25 and 89?years (mean age 55.8?±?15.5). According to different clinical presentation and evolution, related to their unique drainage pattern into the cavernous sinus, we examined the carotid-cavernous fistulas separately from other dural arteriovenous fistulas. Interestingly, we found that the migraine-like headache was the major onset symptom of dural arteriovenous fistulas different from carotid-cavernous fistulas (p?=?0.036). On the other hand, non-migraine-like headache was a typical characteristic of carotid-cavernous fistulas (p?=?0.003). Moreover, ocular symptoms were more frequently observed in carotid-cavernous fistulas (92.9% p?< 0.001). Seventy percent of patients did not report any impact on quality of life (mRS 0 or 1) at follow-up. CONCLUSIONS:These findings suggest a link between the site of lesion and clinical features of the headache, a symptom that usually leads to hospitalization. In particular, ocular symptoms accompanying non-migraine-like headache should be promptly recognized and raise the suspicion of a carotid-cavernous fistula, while migraine-like headache may suggests other dural arteriovenous fistulas. This study provides new significant insights on headache and its characteristics as a presentation symptom in dural arteriovenous fistulas.

Project description:Migraine is a debilitating condition characterized by recurrent severe head pain. Although mechanisms underlying a migraine attack remain controversial, one proposal is that inflammatory mediator (IM)-induced activation and sensitization of dural afferents contribute to the initiation of migraine pain. We and others have shown that the electrophysiological properties of afferents, both in the absence and the presence of IM, vary as a function of target of innervation. These differences may account for unique aspects of pain syndromes associated with specific body regions. Therefore the purpose of the present study was to test the hypothesis that the electrophysiological properties of dural afferents differ from those innervating the temporalis muscle (TM), a structure in close proximity to the dura but that is not associated with pain syndromes at all similar to migraine. Acutely dissociated retrograde labeled primary afferents innervating the dura and TM were examined with whole cell current-clamp recordings. Passive and active electrophysiological properties were determined before and after the application of IM: (in muM) prostaglandin E(2) (1), bradykinin (10), and histamine (1). In the absence of IM, there were significant differences between the two populations, particularly with respect to the response to suprathreshold stimulation where dural afferents were more excitable than TM afferents. Importantly, although both populations of afferents were sensitized by IM, the pattern of passive and active electrophysiological changes associated with IM-induced sensitization of these two populations of afferents suggested that there were both similarities and marked differences between the two with respect to underlying mechanisms of sensitization. If the differences between dural and TM afferents are due to a differential pattern of ion channel expression rather than differences in the relative density/biophysical properties of the same ion channels, it may be possible to selectively treat migraine pain by targeting the distinct mechanisms underlying IM-induced sensitization of dural afferents.

Project description:BackgroundTRPV4 channels are calcium-permeable cation channels that are activated by several physicochemical stimuli. Accordingly, TRPV4 channels have been implicated in the regulation of osmosensing, mechanotransduction, thermosensation, and epithelial/endothelial barrier functions. Whether TRPV4 is also mechanistically implicated in melanoma cell proliferation is not clear. Here, we hypothesized that TRPV4 is expressed in human melanoma and that pharmacological activation interferes with cell proliferation.Methodology/principal findingsTRPV4 functions were studied in melanoma cell lines (A375, SK-MEL-28, MKTBR), immortalized non-cancer keratinocytes (HaCaT), and murine 3T3 fibroblasts by patch-clamp, qRT-PCR, intracellular calcium measurements, cell proliferation, and flow cytometric assays of apoptosis and cell cycle. The selective TRPV4-activator, GSK1016790A, elicited non-selective cation currents with TRPV4-typical current-voltage-relationship in all cell lines. GSK1016790A-induced currents were blocked by the TRPV4-blocker, HC067047. TRPV4 mRNA expression was demonstrated by qRT-PCR. In A375 cells, TRPV4 activation was frequently paralleled by co-activation of calcium/calmodulin-regulated KCa3.1 channels. Light microscopy showed that TRPV4-activation produced rapid cellular disarrangement, nuclear densification, and detachment of a large fraction of all melanoma cell lines and HaCaT cells. TRPV4-activation induced apoptosis and drastically inhibited A375 and HaCaT proliferation that could be partially prevented by HC067047.Conclusions/significanceOur study showed that TRPV4 channels were functionally expressed in human melanoma cell lines and in human keratinocytes. Pharmacological TRPV4 activation in human melanoma cells and keratinocytes caused severe cellular disarrangement, necrosis and apoptosis. Pharmacological targeting of TRPV4 could be an alternative or adjuvant therapeutic strategy to treat melanoma progression and other proliferative skin disorders.

Project description:Importance:Women giving birth have high rates of dural puncture secondary to neuraxial anesthesia and are at high risk for a resulting headache. It appears to be unknown whether there is a significant association between post-dural puncture headache and subsequent intracranial subdural hematoma. Objective:To determine the association of post-dural puncture headache with postpartum intracranial subdural hematoma. Design, Setting, and Participants:This cohort study of patients used hospital discharges recorded in the US Agency for Healthcare Research and Quality National Readmission Database for women who experienced childbirth from January 2010 to December 2016. Patients were included if they had been admitted for childbirth, had 2 months of follow-up data, and did not receive a diagnostic lumbar puncture. Only the first delivery for a calendar year was studied. Data were analyzed from January 2018 to June 2019. Exposures:Women with post-dural puncture headache associated with neuraxial anesthesia in the 2-month postpartum period were identified using International Classification of Disease (Ninth Edition and Tenth Edition) codes and were compared with those without post-dural puncture headaches. Main Outcome and Measures:The primary outcome was intracranial subdural hematoma in the 2-month postpartum period. Secondary outcomes included in-hospital mortality and occurrence of neurosurgery. Results:A total of 26?469?771 patients with 26?498?194 deliveries were included. Exclusion of repeated deliveries (n?=?28?423), deliveries without 2 months of follow-up data (n?=?4?329?621), and deliveries with diagnostic lumbar puncture (n?=?9334) resulted in a final cohort of 22?130?815 patients and deliveries. For the cohort, the mean (SD) age was 28.1 (6.0) years, and there were 68?374 post-dural puncture headaches, for an overall rate of 309 (95% CI, 302-316) per 100?000. There were 342 cases of subdural hematoma identified, indicating a rate of 1.5 (95% CI, 1.3-1.8) per 100?000 women. Of these, 100 cases were in women with post-dural puncture headache, indicating a rate of 147 (95% CI, 111-194) hematoma cases per 100?000 deliveries in this subgroup. Post-dural puncture headache had an unadjusted absolute risk increase of 145 (95% CI, 117-174) subdural hematoma cases per 100?000 deliveries. After adjusting for confounders, post-dural puncture headache had an odds ratio for subdural hematoma of 199 (95% CI, 126-317; P?<?.001) and an adjusted absolute risk increase of 130 (95% CI, 90-169; P?<?.001) per 100?000 deliveries. Conclusions and Relevance:The presence of presumed post-dural puncture headache after neuraxial anesthesia in childbirth, compared with no headache, was associated with a small but statistically significant absolute increase in the risk of being diagnosed with intracranial subdural hematoma. Further research is needed to establish if this association is causal for this rare outcome.

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Activation of TRPV4 on dural afferents produces headache-related behavior in a preclinical rat model.

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Activation of TRPV4 on dural afferents produces headache-related behavior in a preclinical rat model.

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