Sex differences and role of gonadal hormones on glutamate level in the nucleus accumbens in morphine tolerant rats: A microdialysis study

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Abstract

Sex differences are observed in the development of tolerance to the antinociceptive effect of opioid drugs such as morphine, but the precise underlying mechanism remains unclear. There are evidences about the interaction between gonadal hormones and neuromodulatory systems including opioidergic and glutamatergic systems. We examined the sex differences and the role of gonadal hormones on the glutamate level in the nucleus accumbens in morphine tolerant rats using in vivo microdialysis. A microdialysis probe was implanted into the left nucleus accumbens core of rats and CSF (cerebrospinal fluid) dialysates were collected. The concentration of glutamate was measured by high-performance liquid chromatography with a fluorescence detector. The results showed that after chronic morphine administration, tolerance to antinociceptive effects of morphine was significantly greater in male rats (P < 0.001). Sex differences in tolerance to morphine disappeared with gonadectomy of animals. There was also a significant sex difference in the glutamate level in the nucleus accumbens of morphine tolerant rats (P < 0.001), ovariectomy of female rats decreased the glutamate level significantly (P < 0.001), while gonadectomy did not change the glutamate level in males significantly. In conclusion, these experiments demonstrate that the excitatory amino acid release in the nucleus accumbens may be modulated by an estrogen-sensitive mechanism and play a role in the morphine analgesia and tolerance.

Introduction

Previous studies have documented sex differences in the response to opioids drugs including morphine in both humans and laboratory animals. Typically, males display greater degree of antinociception than females (Cicero et al., 1996, Boyer et al., 1998, Kest et al., 1999, Craft and Bernal, 2001). It has also been reported that there are sex differences in the development of tolerance to morphine in rats. Male rats develop greater tolerance than females (Badinllo-martines et al., 1984, Craft et al., 1999). It seems that sex steroids mediate these differences by acting on neuronal processes in CNS (central nervous system) (Cicero et al., 2002, Craft et al., 2004). We did not find any study to report the mechanisms of sex-related differences in tolerance to morphine.

Based on the known role of excitatory amino acids including glutamate and it's receptors in the development of tolerance to opioids (Fundytus and Coderre, 1994, Mao et al., 1994) and the existence of evidence on the potentiating actions of 17-beta estradiol (E2) on glutamate-induced excitation (Smith, 1989), it is supposed that gonadal steroids are responsible for sex-related differences in morphine tolerance via affecting glutamate concentration in CNS.

As the nucleus accumbens is critically involved in the development of tolerance to opioids (Gracy et al., 1997, Schmidt et al., 2002) and there are functional associations between glutamate receptors and morphine in this brain region (Gracy et al., 1997), we proposed that glutamate level changes in nucleus accumbens may bear a relationship with sex differences in morphine tolerance.

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Animals

Male and female Sprague-Dawley rats (180–240 g) were used. All rats were housed in 4–6 per standard cages at room temperature (22 ± 1 °C) on a 12 h light/dark cycle. Food and water were available ad libitum. All procedures in this study, was performed based on ethical guidelines of IASP and approved by the Shaheed Beheshti University of Medical Science Ethics committee.

Surgery

Rats were gonadectomized under sodium pentobarbital (males 45 mg/kg, females 40 mg/kg, i.p.) anesthesia. Females were

Influences of sex and gonadal hormones in the development of tolerance to morphine antinociception

There were no significant sex differences in the baseline tail-flick latencies in intact animals. Gonadectomy of rats did not change the baseline tail-flick latencies in both sexes (Table 1).

As shown in Table 1, morphine produced a significantly greater antinociception in intact males after single dose administration [F(1, 40) = 21.89, P < 0.001]. The sex differences in morphine antinociception were decreased with gonadectomy, somehow, it was not significant. Gonadectomy of animals decreased

Discussion

The results of the present study, showed that acute dose of morphine, has typically greater analgesic activity in male rats than in females. These agree with the results of previous studies in which morphine was a more potent analgesic in male than in female rodents (Mogil et al., 2000, Craft, 2003, Holtman et al., 2004). The magnitude of sex differences in the present study may differ from that reported by some investigators (Cicero et al., 1996, Craft et al., 1999).

These differences may be

Acknowledgements

This research was financially supported by neuroscience research center of Shaheed Beheshti University of Medical Sciences in Iran. Some of this work was presented at the 11th world congress on pain (Sydney, Australia), 21–26 Aug 2005.

References (33)

  • S.S. Smith

    Estrogen administration increases neuronal responses to excitatory amino acids as a long-term effect

    Brain Res.

    (1989)
  • Z.H. Wen et al.

    Increasing of intrathecal CSF excitatory amino acids concentration following morphine challenge in morphine-tolerant rats

    Brain Res.

    (2004)
  • H. Akaola et al.

    Opiate withdrawal-induced hyperactivity of locus soeruleus neurons is substantially mediated by augmented excitatory amino acid input

    J. Neurosci.

    (1991)
  • D. Badinllo-martines et al.

    Monosodium glutamate and analgesia induced by morphine. Test specific effects

    Neuropharmacology

    (1984)
  • R. Bartok et al.

    Sex differences in opioid antinociception

    J. Pharmacol. Exp. Ther.

    (1997)
  • T. Cicero et al.

    Gender-related differences in the antinociceptive properties of morphine

    J. Pharmacol. Exp. Ther.

    (1996)

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