Abstract
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.
Perspective
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.
Key words
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Article info
Publication history
Published online: March 13, 2008
Accepted:
January 5,
2008
Received in revised form:
December 7,
2007
Received:
June 12,
2007
Footnotes
Supported by Abbott Laboratories.
Identification
Copyright
© 2008 American Pain Society. Published by Elsevier Inc. All rights reserved.
