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- Rachel Davis-Taber, Scott Baker, Sonya G Lehto, Chengmin Zhong, Carol S Surowy, Connie R Faltynek, Victoria E Scott, and Prisca Honore.
- Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
- J Pain. 2008 May 1;9(5):449-56.
UnlabelledThe pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC(1)-R) is a member of the 7-transmembrane domain, group 2 G-protein coupled receptor family. PAC(1)-Rs modulate neurotransmission and neurotrophic actions and have been implicated in both pronociception and antinociception. To better understand the role of PAC(1)-Rs in pain, PACAP 6-38, a PAC(1)-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 PAC(1)-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, PAC(1)-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.
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