Abstract
In the adult male Sprague-Dawley rat, a species commonly used to study tolerance to the antinociceptive effects of morphine, ≈10% of the morphine dose is metabolized to normorphine-3-glucuronide (NM3G). In contrast, NM3G is a relatively minor metabolite of morphine in human urine reportedly accounting for ≈1% of the morphine dose. To date, the pharmacology of NM3G has been poorly characterized. Therefore, our studies were designed to determine whether the intrinsic pharmacology of NM3G is similar to that of morphine-3-glucuronide (M3G), the major metabolite of morphine, which has been shown to be a potent central nervous system (CNS) excitant and to attenuate the intrinsic antinociceptive effects of morphine in rats. The CNS excitatory potency of NM3G was found to be approximately half that of M3G, inducing convulsions in rats at intracerebroventricular (i.c.v.) doses of ≥16.8 nmol. When administered before morphine (70 nmol i.c.v.), NM3G (8.9 nmol i.c.v.) attenuated antinociception for up to 2 hr, but when administered after morphine, no significant attenuation of morphine antinociception was observed. Thus, after i.c.v. administration, NM3G like M3G, is a potent CNS excitant and antianalgesic in the rat. NM3G may therefore play a role in the development of tolerance to the antinociceptive effects of morphine in the rat as has been proposed previously for M3G.
Footnotes
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Send reprint requests to: Dr. Maree Smith, School of Pharmacy, The University of Queensland, St. Lucia, Queensland 4072, Australia. E-mail: maree.smith{at}pharmacy.uq.edu.au
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↵1 This work was supported by the Queensland Cancer Fund and by The University of Queensland Research Grants Scheme. G.D.S. was supported by an Australian Postgraduate Award.
- Abbreviations:
- NM3G
- normorphine-3-glucuronide
- M3G
- morphine-3-glucuronide
- i.c.v.
- intracerebroventricular
- SD
- Sprague-Dawley
- AUC
- area under the response vs. time curve
- CNS
- central nervous system
- %MPE
- percentage of the maximum possible antinociceptive effect
- Received September 3, 1997.
- Accepted February 20, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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