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 (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.


CONCLUSIONS
This 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.
Davis-Taber
Rachel
R
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Baker
Scott
S
Lehto
Sonya G
SG
Zhong
Chengmin
C
Surowy
Carol S
CS
Faltynek
Connie R
CR
Scott
Victoria E
VE
Honore
Prisca
P
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement; D010446:Peptide Fragments / Q000494:pharmacology; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*
D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; C075647:pituitary adenylate-cyclase-activating-peptide (6-38)