Central pituitary adenylate cyclase 1 receptors modulate nociceptive behaviors in both inflammatory and neuropathic pain states

J Pain. 2008 May;9(5):449-56. doi: 10.1016/j.jpain.2008.01.329. Epub 2008 Mar 12.


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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism
  • Hyperalgesia / physiopathology
  • Inflammation / drug therapy
  • Inflammation / metabolism*
  • Inflammation / physiopathology
  • Injections, Spinal
  • Ligation
  • Male
  • Neuralgia / drug therapy
  • Neuralgia / metabolism*
  • Neuralgia / physiopathology
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / metabolism
  • Nociceptors / drug effects
  • Nociceptors / metabolism*
  • Nociceptors / physiopathology
  • Pain Measurement
  • Peptide Fragments / pharmacology
  • Peripheral Nerves / drug effects
  • Peripheral Nerves / metabolism
  • Peripheral Nerves / physiopathology
  • Peripheral Nervous System Diseases / drug therapy
  • Peripheral Nervous System Diseases / metabolism*
  • Peripheral Nervous System Diseases / physiopathology
  • Pituitary Adenylate Cyclase-Activating Polypeptide / agonists
  • Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism
  • Pituitary Adenylate Cyclase-Activating Polypeptide / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / antagonists & inhibitors
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / metabolism*


  • Peptide Fragments
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
  • pituitary adenylate-cyclase-activating-peptide (6-38)