Imipramine-fentanyl antinociception in a rabbit tooth pulp model.
Antinociception of imipramine (I) and its effect in combination with fentanyl (F) was evaluated in rabbits using electrically-induced lick chew responses via tooth pulp stimulation as the model of nociception. Acute i.v. injections of I elicited a graded dose response comparable to i.v. morphine (M) with I ED 50 = 4.35 mg/kg (2.31-8.14, 95% CL) and M ED 50 = 1.81 mg/kg (1.11-3.90), with no differences in the slopes between the two curves. The lethal dose of I was 10 mg/kg. An i.v. dose of I twice the ED 50 elicited an antinociceptive effect of more than 50% maximum possible effect (MPE) for 90 minutes with peak effect of 82% MPE occurring at 15 minutes. These effects of I were not reversed by a morphine-reversal dose of naloxone (0.1 mg/kg i.v.) but were reversed with a ten fold dose of naloxone. F ED 50 values (mcg/kg) were lowered from 11.35 to 2.70, 0.74 and 0.33 with increasing pretreatment doses of I (1.0, 2.1 and 3.2 mg/kg). These magnitudes of potency increases of F were 4.2, 15.3 and 34.4 fold respectively. A single i.v. ED 50 dose of I extended the time to 50% MPE of an ED 90 dose of F from 26 minutes to 77 minutes; of a 2 X ED 50 dose of F from 17 minutes to 28 minutes. Data points for three different combinations of I and F fell significantly within the synergistic field of an ED 50 isobologram and a polynomial equation described the curve best fitting the data points. F alone (i.v. ED 50 dose) increased the PaCO2 values to 74% above controls and three different combinations with I showed no increases in PaCO2 values above controls. I alone did not significantly cause any change in PaCO2 values from controls.
Bergman
S A
SA
Department of Pharmacology, Dental School, University of Maryland, Baltimore 21201.
Wynn
R L
RL
Alvarez
L
L
Asher
K
K
Thut
P D
PD
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002245:Carbon Dioxide / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D004558:Electric Stimulation; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage / Q000494:pharmacology*; D007099:Imipramine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects*; D011817:Rabbits; D012119:Respiration / Q000187:drug effects
D000700:Analgesics; D004338:Drug Combinations; D002245:Carbon Dioxide; D009270:Naloxone; D009020:Morphine; D007099:Imipramine; D005283:Fentanyl