Central Pituitary Adenylate Cyclase 1 Receptors Modulate Nociceptive Behaviors in Both Inflammatory and Neuropathic Pain States

The pituitary adenylate cyclase–activating polypeptide type 1 receptor (PAC1-R) is a member of the 7-transmembrane domain, group 2 G-protein coupled receptor family. PAC1-Rs modulate neurotransmission and neurotrophic actions and have been implicated in both pronociception and antinociception. To better understand the role of PAC1-Rs in pain, PACAP 6-38, a PAC1-R antagonist, was evaluated in several inflammatory and neuropathic pain models after intrathecal (i.t.) administration. PACAP 6-38 potently reduced mechanical allodynia in a neuropathic spinal nerve ligation model (77% ± 15% maximal effect at 12 nmol, P < .01) and was also effective in reducing thermal hyperalgesia in the carrageenan model of inflammatory pain (89% ± 17% maximal effect at 12 nmol, P < .01). Although nociceptive responses were also attenuated with PACAP 6-38 in a dose-dependent manner in models of chronic inflammatory and persistent pain, no effects on motor performance were observed at analgesic doses. Taken together, these data demonstrate that blockade of the PAC1-R/PACAP complex by PACAP 6-38 can effectively attenuate thermal hyperalgesia and mechanical allodynia associated with inflammatory and neuropathic pain states. These results further emphasize that at the level of the spinal cord, PAC1-R activation is pronociceptive.PerspectiveThis article presents the analgesic profile generated by the blockade, at the spinal cord level, of the PAC-1 receptor by a potent peptide antagonist. This comprehensive data set demonstrates that if small molecule PAC-1 receptor antagonists could be identified, they would potentially produce broad-spectrum analgesia in both inflammatory and neuropathic pain states.