Abstract
The antinociceptive and ventilatory effects of morphine and other opioid agonists were determined in three rhesus monkeys during a period of morphine maintenance, as well as before and after the chronic exposure to morphine. Before the onset of the daily dosing regimen, morphine increased tail-withdrawal latencies from 50°C water, with an ED50 of 6.4 ± 2.1 mg/kg. Daily injection of 3.2 mg/kg morphine produced a rightward displacement of the morphine dose-response curve, increasing the ED50 of morphine to 28.4 ± 12.3 mg/kg. Doubling the daily morphine dose to 6.4 mg/kg resulted in a further shift to the right of the dose-response curve of morphine. After cessation of the daily dosing regimen, the morphine dose-response curve for producing antinociceptive effects returned toward baseline. The antinociceptive effects of thekappa opioid agonist, ethylketazocine, were similar during the period of daily exposure to morphine, and after cessation of the daily dosing regimen. Before the onset of the daily dosing regimen, morphine, ethylketazocine, fentanyl, butorphanol and nalbuphine decreased ventilation in the presence of air or air mixed with CO2. The baseline ED50 value of morphine for decreasing minute volume in the presence of 5% CO2 was 2.9 ± 0.8 mg/kg. The ventilatory effects of morphine and othermu opioid agonists tested were not attenuated during the daily morphine-dosing regimen. After 40 weeks of daily injections of 3.2 mg/kg morphine, the ED50 of morphine for decreasing minute volume in 5% CO2 was 2.3 ± 1.0 mg/kg, and when the daily dose was doubled to 6.4 mg/kg morphine, the ED50 of morphine was 1.5 ± 0.5 mg/kg. The ventilatory depressant effects of the daily injection 3.2 mg/kg morphine were also unchanged during morphine maintenance. The differential development of tolerance to the antinociceptive and ventilatory effects of morphine demonstrates a separation of these two mu opioid agonist effects in rhesus monkeys.
Footnotes
-
Send reprint requests to: Carol A. Paronis, Harvard Medical School, ADARC-McLean Hospital, 115 Mill St., Belmont, MA 02178-9108.
-
↵1 This work was supported by USPHS grants DA00254, DA 07268 and DA 05653 from NIDA.
-
↵2 Preliminary results were presented at the 56th annual meeting of the College on Problems of Drug Dependence, Palm Beach, FL, 1994.
- Abbreviations:
- M.P.E.
- maximum possible effect
- EKC
- ethylketazocine
- ANOVA
- analysis of variance
- f,breathing frequency
- VT, tidal volume
- VE
- minute volume
- Received October 16, 1996.
- Accepted March 31, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|