Studies of morphine and D-ala2-D-leu5-enkephalin (DADLE) cross-tolerance after continuous intrathecal infusion in the rat.
To determine the cross tolerance to the antinociceptive effects of mu and delta opioids in the spinal cord, rats received a 7-day infusion of one of three concentrations each of morphine (2, 6, or 20 nmol/h) or D-ala2-D-leu5-enkephalin (DADLE) (2, 6, or 20 nmol/h). A constant-rate (1 microliter/h), constant-dose intrathecal infusion pump was used. On day 7, the magnitude of tolerance was assessed by establishing dose-response curves for the effect of the chronic drug given as an intrathecal bolus. Cross-tolerance was assessed in separate groups of animals with identical infusions by establishing morphine dose-response curves in DADLE-tolerant animals and DADLE dose-response curves in morphine-tolerant animals. Each infused animal was used for a single bolus injection. For morphine and DADLE tolerance, a parallel rightward shift in the dose-response curve was produced with the degree of shift proportional to the log of the infusion dose. Thus, at the infusion rate of 6 nmol/h for either morphine or DADLE, the shift of the tolerance dose-response curves was 55- and 33-fold, respectively. Morphine and DADLE cross-tolerance was also detected as shown by rightward shifts of the cross-tolerance dose-response curves; however, these shifts were relatively minor compared to the shifts seen in the tolerance dose-response curves of animals tested with the same agent as infused.(ABSTRACT TRUNCATED AT 250 WORDS)
Stevens
C W
CW
Department of Physiology and Pharmacology, College of Osteopathic Medicine, Oklahoma State University, Tulsa.
Yaksh
T L
TL
D000698:Analgesia; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D016308:Enkephalin, Leucine-2-Alanine; D007278:Injections, Spinal; D008297:Male; D009020:Morphine; D051381:Rats; D011919:Rats, Inbred Strains
D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine