Pain
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The mechanism by which intramuscular injection of BoNTA into the craniofacial muscles decreases migraine headaches is not known. In a blinded study, the effect of BoNTA on the mechanical and chemical responsiveness of individual temporalis muscle nociceptors and muscle neurogenic vasodilation was investigated in female rats. Mechanical threshold was measured for 3h following intramuscular injection of BoNTA or vehicle, and for 10 min after a subsequent injection of the algogen glutamate. ⋯ Additional electrophysiology experiments examined the effect of antagonists for NMDA, CGRP and NK1 receptors on glutamate-induced effects. Glutamate-induced mechanical sensitization was only blocked by the NMDA receptor antagonist, but muscle neurogenic vasodilation was attenuated by NMDA or CGRP receptor antagonists. These data suggest that injection of BoNTA into craniofacial muscles acts to decrease migraine headaches by rapidly decreasing the mechanical sensitivity of temporalis muscle nociceptors through inhibition of glutamate release and by attenuating the provoked release of CGRP from muscle nociceptors.
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The impact of persistent inflammation on voltage-activated Ca(2+) channels in cutaneous DRG neurons from adult rats was assessed with whole cell patch clamp techniques, sqRT-PCR and Western blot analysis. Inflammation was induced with a subcutaneous injection of complete Freund's adjuvant (CFA). DiI was used to identify DRG neurons innervating the site of inflammation. ⋯ An increase in both α2δ1 and Ca(V)2.2 protein was detected in the central nerves arising from L4 and L5 ganglia ipsilateral to the site of inflammation. In current clamp experiments on small and medium diameter cutaneous DRG neurons from naïve rats, blocking ∼40% of HVA current with Cd(2+) (5μM), had opposite effects on subpopulations of cutaneous DRG neurons (increasing excitability and action potential duration in some and decreasing excitability in others). The alterations in the density and distribution of voltage-activated Ca(2+) channels in subpopulations of cutaneous DRG neurons that develop following CFA injection should contribute to changes in sensory transmission observed in the presence of inflammation.
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The change with age in pain perception in humans and the nociceptive behaviors in animals elicited by noxious stimuli to the skin are not well understood, and little is known about the peripheral neural mechanisms of cutaneous nociception in the aged. We systematically examined cutaneous nociceptor responses and nociceptive behaviors in young (9-14 w) and in aged (127-138 w) Sprague-Dawley rats. C-fiber nociceptors in the skin were identified by mechanical and electrical stimulation, and extracellularly recorded from hind paw skin-saphenous nerve preparations in vitro. ⋯ This showed for the first time that not only receptive properties of afferent terminals but also membrane properties of conducting axons are changed in aged rats. Nociceptive behaviors in response to noxious levels of cold (cold plate test) and heat (Hargreaves' radiant heat test) were facilitated in aged animals, while mechanical sensitivity measured by von Frey hairs remained unchanged. These discrepancies between the changes in peripheral afferents and the behavioral outcomes might be explained by facilitatory changes in the central nervous system.