P2X7 receptor blockade reverses purinergic facilitation of neck muscle nociception in mice

Introduction: Facilitation of neck muscle nociception mediated via purinergic signalling may play a role in the pathophysiology of tension-type headache (TTH). The present study addressed reversal of purinergic facilitation of brainstem nociception via P2X7 antagonist action in anaesthetized mice. Methods: Following administration of alpha,beta-meATP (i.m. 20 A mu L/min, 20 A mu L each) into semispinal neck muscles, the impact of neck muscle nociceptive input on brainstem processing was monitored by the jaw-opening reflex in anaesthetized mice (n = 20). The hypothesized involvement of the P2X7 receptor in the alpha,beta-meATP effect was addressed with i.p. (systemic) and i.m. (semispinalis, 20 A mu L/min, 20 A mu L each) administration of P2X7 inhibitor A438079 during established facilitation; i.p. saline served as control. Results: alpha,beta-meATP reliably induced jaw-opening reflex facilitation (256 +/- 48% (mean +/- SEM), n = 20). I.p. A438079 (150, 300 A mu mol/kg) completely reversed this alpha,beta-meATP effect dose-dependently. Neither saline nor intramuscular A438079 (100 A mu M) altered facilitated brainstem nociceptive processing. Discussion: These data suggest that muscular structures are not directly involved in the P2X7 antagonist-mediated reversal of purinergic facilitation. Instead, involvement of neuronal structures, particularly of the central nervous system, seems more probable. The results from this animal experimental model may point to involvement of purinergic P2X7 receptors in TTH pathophysiology and may suggest potential future targets for its pharmacological treatment.