Stimulus trials for testing changes in mechanical sensitivity consisted of graded square-wave stimuli (100-ms rise time, 2-s width, 60-s interstimulus interval) delivered in ascending order

Stimulus trials for testing changes in mechanical sensitivity consisted of graded square-wave stimuli (100-ms rise time, 2-s width, 60-s interstimulus interval) delivered in ascending order. throbbing pain of migraine. == Mouse monoclonal to STYK1 Results == We found that meningeal application of IL-1 leads to the activation and mechanical sensitization of about 70% and 45% of the nociceptors respectively. In contrast, IL-6 was a very poor modulator of meningeal nociceptors’ response properties affecting overall only about 20% of the nociceptors. == Conclusions == Our study provides for the first time in vivo electrophysiological evidence that meningeal action of IL-1 can promote the activation and increased mechanosensitivity of intracranial meningeal nociceptors and that IL-6 generally lacks these properties. Future studies are required to examine the mechanism that plays a role in mediating the nociceptive effects of IL-1 on meningeal nociceptors, which may serve as a target for migraine therapy. Keywords:IL-1, IL-6, Meningeal nociceptor, headache, sensitization, inflammation == Introduction == Activation and enhanced responsiveness to natural stimuli (i.e. sensitization) of primary afferent nociceptors that innervate the intracranial meninges are thought to serve as the neural substrate that underlies the development of migraine as well as other headaches of intracranial origin (14). The exact cellular and molecular mechanisms that drive this nociceptor plasticity are incompletely understood, although meningeal action of proinflammatory algesic mediators is likely to play an BY27 important role (5). Among the mediators thought to contribute to the activation and sensitization of nociceptors are the proinflammatory cytokines tumor necrosis factor alpha (TNF), interleukin 1 beta (IL-1) and interleukin 6 (IL-6), which are released primarily by resident and infiltrating immune cells. The level of these cytokines increases in the internal jugular blood during the first hours of a migraine attack (6), suggesting their potential ability to interact with meningeal nociceptors and promote migraine headache. We have shown recently that meningeal action of one of these cytokines (TNF) can increase the mechanosensitivity of meningeal nociceptors, through a local vascular action (7), and proposed that this cellular mechanism may be important in promoting the painful throbbing sensation during migraine. The aim of the current study was to further examine the potential role of proinflammatory cytokines in headache by determining whether IL-1 and IL-6 can also act upon meningeal nociceptors and promote their activation and increased mechanosensitivity. Previousin vitroelectrophysiological studies have shown that local application of IL-1 to the cell body of small-diameter sensory neurons in dorsal root ganglia can potentiate heat-evoked currents (8), increase sodium currents and evoke action potentials (9). However, whether IL-1 can act upon nociceptorsin vivo, particularly at the level of their peripheral nerve endings to promote sensitization and activation has never been tested. Putative pronociceptive effects of IL-6 on sensory nociceptive neurons were also demonstratedin vitro(10). However,in BY27 vivoelectrophysiological studies indicated that the ability of IL-6 to sensitize nociceptors (at least to heat stimuli) requires the co-presence of BY27 its soluble receptor (1113). Whether IL-6 can act within the intracranial meninges to activate or mechanically sensitize nociceptors is not known. Given the potential role of IL-1 and IL-6 in mediating migraine headache, we investigated for the first time, using anin vivopreparation, whether these proinflammatory cytokines can activate or increase the mechanosensitivity of meningeal nociceptors. == Materials and methods == == Animals == Sprague Dawley male rats (250350 g) were used in compliance with the experimental protocol approved by the institutional Animal Care and Use Committee of the Beth Israel Deaconess Medical Center and adhered to the guidelines of the Committee for Research and Ethical Issues of the International Association for the Study of Pain (14). == Electrophysiological recordings == Rats were deeply anesthetized with urethane (1.51.8 g/kg). Single-unit recordings of meningeal nociceptors in the trigeminal ganglion were conduced as previously described (15,16). Briefly, a craniotomy was made to expose the left BY27 transverse sinus, as well as the adjacent dura. The dura was kept moist using local perfusion with modified synthetic interstitial fluid (SIF; 135 mM NaCl, 5 mM KCl, 1 mM MgCl2, 5 mM CaCl2, 10 mM glucose and 10 mM HEPES, pH 7.2). SIF was also used as the vehicle for all drug testing. For single-unit recording, a platinum-coated tungsten microelectrode (impedance approximately 150 KOhm; FHC Inc., Bowdoin, Maine, USA) was inserted into the left trigeminal ganglion and meningeal nociceptors were identified by their constant latency responses to electrical stimuli (0.5 ms pulse, 0.55 mA, 0.5 Hz) applied to the transverse sinus. Based on their conduction velocity (CV), units were classified as either A delta (CV > 1.5 m/s) or C (CV 1.5 m/s) units. Action potentials were acquired.

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