PD134308, a selective antagonist of cholecystokinin type B receptor, enhances the analgesic effect of morphine and synergistically interacts with intrathecal galanin to depress spinal nociceptive reflexes.
The effects of systemic PD134308 [0.1-3 mg/kg; an antagonist of the cholecystokinin (CCK) type B receptor], morphine, and intrathecal (i.t.) galanin (GAL) on the excitability of the spinal nociceptive flexor reflex and in the hot plate test were examined in rats. PD134308 caused a weak naloxone-reversible depression of the flexor reflex and a moderate antinociceptive effect in the hot plate test. However, PD134308 significantly potentiated the antinociceptive effect of morphine as well as its depressive effect on the flexor reflex. PD134308 and i.t. GAL synergistically depressed the flexor reflex, an effect that was reversed by naloxone. Finally, the magnitude and duration of the depression of the flexor reflex by morphine were synergistically increased by coadministering PD134308 and GAL i.t. The results demonstrated that a CCK antagonist directed to the central CCK type B receptor potentiates the analgesic effects of opioids and nonopioid drugs at the spinal level, thus supporting the notion that CCK in the central nervous system may be an endogenous, physiological opioid antagonist.
Department of Clinical Physiology, Karolinska Institute, Huddinge, Sweden.
Z
Z
Wiesenfeld-Hallin
X J
XJ
Xu
J
J
Hughes
D C
DC
Horwell
T
T
Hökfelt
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002766:Cholecystokinin / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D019004:Galanin; D007211:Indoles / Q000494:pharmacology*; D007278:Injections, Spinal; D007700:Kinetics; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000503:physiopathology; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011949:Receptors, Cholecystokinin / Q000187:drug effects*; D012018:Reflex / Q000187:drug effects; D013012:Sorbitol / Q000031:analogs & derivatives*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D000700:Analgesics; D007211:Indoles; D010455:Peptides; D011949:Receptors, Cholecystokinin; C065599:PD 134308; D009270:Naloxone; D013012:Sorbitol; D008536:Meglumine; D009020:Morphine; D019004:Galanin; D002766:Cholecystokinin