Hunting for origins of migraine pain: cluster analysis of spontaneous and capsaicin-induced firing in meningeal trigeminal nerve fibers.

A Zakharov,D Fayuk,N Naumenko,I Shelukhina,R Khazipov,R Giniatullin,K Koroleva,E Kilinc,C Vitale,A Skorinkin

doi:10.3389/fncel.2015.00287

Abstract

Trigeminal nerves in meninges are implicated in generation of nociceptive firing underlying migraine pain. However, the neurochemical mechanisms of nociceptive firing in meningeal trigeminal nerves are little understood. In this study, using suction electrode recordings from peripheral branches of the trigeminal nerve in isolated rat meninges, we analyzed spontaneous and capsaicin-induced orthodromic spiking activity. In control, biphasic single spikes with variable amplitude and shapes were observed. Application of the transient receptor potential vanilloid 1 (TRPV1) agonist capsaicin to meninges dramatically increased firing whereas the amplitudes and shapes of spikes remained essentially unchanged. This effect was antagonized by the specific TRPV1 antagonist capsazepine. Using the clustering approach, several groups of uniform spikes (clusters) were identified. The clustering approach combined with capsaicin application allowed us to detect and to distinguish “responder” (65%) from “non-responder” clusters (35%). Notably, responders fired spikes at frequencies exceeding 10 Hz, high enough to provide postsynaptic temporal summation of excitation at brainstem and spinal cord level. Almost all spikes were suppressed by tetrodotoxin (TTX) suggesting an involvement of the TTX-sensitive sodium channels in nociceptive signaling at the peripheral branches of trigeminal neurons. Our analysis also identified transient (desensitizing) and long-lasting (slowly desensitizing) responses to the continuous application of capsaicin. Thus, the persistent activation of nociceptors in capsaicin-sensitive nerve fibers shown here may be involved in trigeminal pain signaling and plasticity along with the release of migraine-related neuropeptides from TRPV1 positive neurons. Furthermore, cluster analysis could be widely used to characterize the temporal and neurochemical profiles of other pain transducers likely implicated in migraine.

Highlights

Migraine is the most common neurological disease, but the exact neurobiological mechanisms leading to migraine pain are not well understood
The main findings of the present study are: (i) variable contribution of individual fibers to ongoing firing in control and during activation of nociceptors by the transient receptor potential vanilloid 1 (TRPV1) agonist capsaicin; (ii) almost full block of spontaneous or capsaicin-evoked spikes by TTX; and (iii) two mechanisms contributing to persistent capsaicininduced activity of the trigeminal nerve involving sustained activity of capsaicin responses in individual fibers
Characterization of Preparation and the Recording Mode Since migraine headache originates from trigeminal nerve terminals in meninges (Goadsby, 2007; Levy, 2010) it is important to have a direct experimental approach to study these structures in live tissues

Summary

Introduction

Migraine is the most common neurological disease, but the exact neurobiological mechanisms leading to migraine pain are not well understood. A widely held view suggests that migraine headaches originate from the activation of trigeminal nerve terminals in meninges followed by neuronal sensitization via release of migraine mediators (Goadsby, 2007; Levy, 2010) such as calcitonin gene related peptide (CGRP; Giniatullin et al, 2008). Meningeal tissues are innervated by peripheral branches of the trigeminal nerve consisting mainly of nociceptive non-myelinated C- and thin myelinated Aδ-fibers (Strassman and Levy, 2006). The typical feature of nociceptive peptidergic C-fibers is an expression of capsaicin sensitive transient receptor potential vanilloid 1 (TRPV1) receptors (Julius and Basbaum, 2001; Moran et al, 2011), which serve as an integrator of various chemical, mechanical and temperature pain signals. While well studied in the somata of cultured neurons, TRPV1 receptor mediated signaling and the functional role of TRPV1 receptor desensitization in the peripheral nerve terminals remains unknown

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