Activation and sensitization of meningeal nociceptors by PACAP-38: implications for migraine headache.

Emerging evidence implicates pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) in migraine and other headache disorders. Systemic infusion of PACAP-38 induces migraine headache in people with migraine and mild headache in healthy adults. However, the precise mechanism and site of action remain poorly characterized. To address this gap, we assessed whether PACAP-38 elicits headache by activating meningeal nociceptors. In vivo single-unit electrophysiological recordings were obtained from C- and Aδ-meningeal nociceptors in the trigeminal ganglion of anaesthetized male and female rats. Spontaneous firing rates and mechanical responses to dural indentation with von Frey filaments were recorded before and for 4 h after a 20-min intracarotid infusion of PACAP-38 (1 µg/ml/kg, 10 µg/ml/kg and 100 µg/ml/kg) or vehicle (isotonic saline). At the human-equivalent dose (10 µg/ml/kg), PACAP-38 activated 15 of 30 (50%) neurons, compared with none after vehicle (P < 0.01). Activation rates did not differ between C-fibres (7 of 17; 41%) and Aδ-fibres (8 of 13; 61.5%). The lowest dose of PACAP-38 (1 µg/ml/kg) activated 3 of 9 (33%) neurons, whereas the highest dose (100 µg/ml/kg) activated all four tested neurons, including two C-fibres and two Aδ-fibres. These results suggest that PACAP-38 induces headache through peripheral activation of meningeal nociceptors rather than exerting direct central effects within the spinal trigeminal nucleus.