Articles
Gender Differences in the Reinforcing Properties of Morphine

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Abstract

The purpose of the present studies was to examine whether gender differences could be observed in an important aspect of morphine's pharmacology: its reinforcing properties. Our results showed that morphine served as a positive reinforcing agent in both male and female rats in a place conditioning paradigm, but that the dose–response curves displayed marked sex-related differences. At doses from 0.2 up to 10.0 mg/kg, morphine induced an equally strong preference for the drug-associated chamber in males and females. However, as the dose was increased from 10–17.5 mg/kg, morphine ceased to act as a positive reinforcer in males. In contrast, a very strong preference for the morphine-associated chamber was still observed in females at doses up to 30 mg/kg. No gender differences in the blood and brain levels of morphine were observed subsequent to morphine administration during the conditioning phase, suggesting that pharmacokinetic factors were not involved in the sex-related differences observed. Consequently, these results suggest that there are intrinsic sex-linked differences in the doses of morphine that can induce a preference for the drug-associated chamber in a place-conditioning paradigm that are most likely related to differences in the sensitivity of the central nervous system to morphine's reinforcing properties in males and females.

Section snippets

Materials

Sprague–Dawley derived rats were purchased from Harlan–Sprague–Dawley, Indianapolis, IN. They were used at 70–90 days of age at the start of all studies described in this article. Morphine-sulfate was purchased from Sigma Chemical Co., St. Louis, MO. The place preference apparatus was custom made to our specifications by MedAssociates (Lafayette, IN), and is described in more detail below. The iodinated morphine radioimmunoassay kit was purchased from Diagnostic Products Corporation (Los

General Considerations Regarding the Place-Conditioning Paradigm

During the acclimation phase both male and female rats displayed a preference for the black chamber, with females showing a significantly greater preference than males (time spent in white − time spent in black): −122.1 (±19.6) s vs. −26.35 (±15.81) s, respectively. On the basis of these findings, morphine injections were generally paired with the nonpreferred white chamber, and saline with the preferred black chamber. However, in eight groups of males and females, the morphine-associated

Discussion

The results of these studies demonstrate significant sex-related differences in the positive reinforcing properties of morphine. Although morphine served as a positive reinforcer in both males and females, the dose–response curves were markedly different. At doses from 0.2 to 10.0 mg/kg, morphine induced a strong preference for the drug-associated chamber in both males and females, but as the dose was increased from 10–17.5 mg/kg, the preference for the drug-associated chamber declined sharply

Acknowledgements

This research was supported in part by USPHS Grants DA03833 (T.J.C.), DA09140 (T.J.C.), and DA09344 (B.N.) from the National Institute on Drug Abuse.

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    Justin Ogden was supported by the Department of Molecular Biology and Pharmacology at Washington University School of Medicine.

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