The cholecystokinin receptor antagonist devazepide enhances morphine-induced analgesia but not morphine-induced respiratory depression in the squirrel monkey.
The effects of the cholecystokinin antagonist devazepide on analgesia and respiratory depression induced by morphine in squirrel monkeys were examined. Pain thresholds were determined using the tail withdrawal procedure, in which monkeys restrained in chairs kept their tails in cool (35 degrees C) water for at least 20 sec, but withdrew them from warm (55 degrees C) water in less than 4 sec. Morphine produced a dose-related increase in tail withdrawal latencies from warm water. Devazepide (injected i.p. or p.o.) had no effect on tail withdrawal latencies when given alone but enhanced the analgesic effects of morphine. The devazepide dose-response curve for morphine enhancement was bell-shaped with doses of 3, 10, 30 and 100 micrograms/kg injected i.p. increasing morphine analgesia whereas higher and lower dose did not. In a separate group of monkeys, morphine produced dose-dependent decreases in respiratory rate and oxygen tension and increases in carbon dioxide tension. In contrast to its effects on morphine analgesia, devazepide had no effect on the various indices of morphine-induced respiratory depression. These data suggest that devazepide may have therapeutic utility as an adjuvant to morphine analgesia allowing lower dose of the opiate to be used to relieve pain and reducing the risk of opiate-induced respiratory depression.
Dourish
C T
CT
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, England.
O'Neill
M F
MF
Schaffer
L W
LW
Siegl
P K
PK
Iversen
S D
SD
D000284:Administration, Oral; D000698:Analgesia; D000818:Animals; D001570:Benzodiazepinones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D020109:Devazepide; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007274:Injections, Intraperitoneal; D008297:Male; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement / Q000379:methods; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012120:Respiration Disorders / Q000139:chemically induced*; D012453:Saimiri
D001570:Benzodiazepinones; D011949:Receptors, Cholecystokinin; D009270:Naloxone; D009020:Morphine; D002766:Cholecystokinin; D020109:Devazepide