Modulation of nociceptive transmission by pituitary adenylate cyclase activating polypeptide in the spinal cord of the mouse

Pain. 2002 Nov;100(1-2):27-34. doi: 10.1016/s0304-3959(02)00207-5.


Superficial layers of the dorsal horn receive a dense plexus of nerve fibers immunoreactive to pituitary adenylate cyclase activating polypeptide (PACAP). In vivo experiments were conducted in the mice to evaluate the effects of PACAP-38, herein referred to as PACAP, PACAP receptor antagonist PACAP(6-38) and PACAP-antiserum on nociceptive behaviors induced by radiant heat, intrathecally administered N-methyl-D-aspartate (NMDA) or intraplantarly administered formalin. PACAP (0.05-0.5 microg) dose-dependently decreased the paw-withdrawal latencies induced by thermal stimulation and enhanced the aversive licking and biting behaviors induced by intrathecally injected NMDA. Pretreatment with the PACAP receptor antagonist PACAP(6-38) (0.5-2 microg) or PACAP-antiserum (1:500-2,000 dilution) dose-dependently attenuated the second phase, but not the first phase, of nociceptive responses to formalin. Next, the effects of PACAP on NMDA- and kainate-induced currents evoked in single dorsal horn neurons were studied. Whole-cell patch recordings were made from superficial dorsal horn neurons of spinal cord slices from 14- to 20-day-old mice. PACAP at the concentrations of 100 and 200 nM, which caused no significant change of holding currents, increased NMDA-but not kainate-induced currents in superficial dorsal horn neurons. Our results suggest that exogenously applied PACAP sensitizes the dorsal horn neurons to formalin stimulation, and facilitates NMDA receptor-mediated nociceptive response. As a corollary, PACAP, which may be released from primary afferent fibers potentiates nociceptive transmission to the dorsal horn by interacting primarily with NMDA receptors.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Behavior, Animal / drug effects
  • Excitatory Amino Acid Agonists / pharmacology
  • Hot Temperature
  • Injections, Spinal
  • Male
  • Membrane Potentials / drug effects
  • Mice
  • Mice, Inbred ICR
  • N-Methylaspartate / pharmacology
  • Neurons, Afferent / physiology
  • Neuropeptides / immunology
  • Neuropeptides / pharmacology*
  • Nociceptors / drug effects*
  • Nociceptors / physiology*
  • Pain Measurement
  • Pain Threshold / drug effects
  • Peptide Fragments / pharmacology*
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Substantia Gelatinosa / cytology
  • Substantia Gelatinosa / physiology*


  • Adcyap1 protein, mouse
  • Antibodies
  • Excitatory Amino Acid Agonists
  • Neuropeptides
  • Peptide Fragments
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • pituitary adenylate-cyclase-activating-peptide (6-38)
  • N-Methylaspartate