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

Background: 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). Methods: 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. Results: These studies found that 56% and 49% of identified dural afferents generate currents in response to hypotonic solutions and 4α-PDD, respectively. The response to these stimuli indicates that dural afferents express TRPV4. Activation of meningeal TPRV4 using hypotonic solution or 4α-PDD in vivo resulted in both facial and hind paw allodynia that was blocked by the TRPV4 antagonist RN1734. Conclusion: These data indicate that activation of TRPV4 within the meninges produces afferent nociceptive signaling from the head that may contribute to migraine headache.