Characterization of the antinociceptive effect of oxycodone in male and female rats

Abstract

A number of investigators have shown that sex plays an important role in the analgesic effects of opioids. Typically, the antinociceptive responsiveness to mu opioid agonists such as morphine is greater in male than in female rats. The effect of sex on kappa opioid analgesia is less known. The present study was conducted to examine sex-related differences in responsiveness to oxycodone (putative kappa/mu opioid agonist). This information is important since oxycodone is widely used clinically for treatment of pain. The present results indicated that oxycodone had a greater antinociceptive response in female rats compared to male rats. This sex specific responsiveness to oxycodone, however, was lost with chronic administration. The greater antinociception in female rats was even more prominent with U50,488H (selective kappa agonist). Further, low (subanalgesic) doses of oxycodone and U50,488H enhanced the sensitivity to pain (hyperalgesia) to a greater extent in male than in female rats. This is in contrast to the previously shown greater hyperalgesic effect of subanalgesic doses of the mu opioid agonist, morphine, in female than in male rats. The present findings suggest that sexual dimorphism in the effect of opioids is related to the opioid receptors on which they predominately act.

Introduction

Sex-related differences in pain perception and pain inhibition have recently received a great deal of attention (see Fillingim and Gear, 2004 for review). A number of studies have determined the responsiveness to mu opioid agonists (such as morphine) in relation to sex in rodents and humans. Typically, male rats have been observed to be more sensitive to morphine than female rats (see Craft, 2003a, Craft, 2003b, Kest et al., 2000, Miaskowski et al., 2000 for review). In contrast, the effect of sex on the antinociceptive action of kappa opioid agonists remains equivocal as only a few animal studies have compared the antinociception produced by these opioids with respect to sex. The results of these studies are conflicting (Bartok and Craft, 1997, Craft et al., 1998, Craft and Bernal, 2001, van Haaren et al., 2000, Stoffel et al., 2005, Tershner et al., 2000).

Oxycodone, a commonly used opioid, appears to exert its antinociceptive effect by action at the kappa opioid receptors in male rats (Ross and Smith, 1997, Ross et al., 2000). However, oxycodone has been shown to bind with greater selectivity to mu than kappa receptors in brain homogenates from male mice (Yoburn et al., 1995). Furthermore, there is a line of evidence that oxycodone has mu opioid agonist properties with abuse liability similar to morphine (Beardsley et al., 2004, Zacny and Gutierrez, 2003). Oxycodone has been reported to have an antinociceptive potency comparable to morphine with fewer side effects (Bruera et al., 1998, Kalso et al., 1991, Heiskanen and Kalso, 1997) and it is available in the slow release form for convenient oral dosing. Despite decades of wide clinical use of oxycodone for the treatment of acute and chronic pain, relatively little is known about its pharmacological properties. In particular, we are aware of no data regarding the sex-related differences in oxycodone antinociception and tolerance.

Therefore, the present study was conducted to determine the antinociceptive effect of oxycodone after its acute and chronic administration in male and female rats (tail-flick test). For comparative purposes, the antinociceptive effect of the selective kappa agonist, U50,488H was tested. We have previously found that subanalgesic doses of the mu opioid, morphine, produced hyperalgesia and that this effect was blocked by the N-methyl-d-aspartate (NMDA) receptor antagonist, ketamine (Holtman and Wala, 2005). In the present study we wanted to see if this phenomenon extended to other opioid receptor subtypes. Therefore, the pain enhancing properties (hyperalgesic) of oxycodone and U50,488H were examined after administration of low (subanalgesic) doses of these opioids alone and in combination with (±)-ketamine. Finally, since motor impairment may affect the response to noxious stimuli, motor activity was also evaluated after administration of oxycodone and U50,488H in male and female rats. The findings of the present rodent study may have implications for the use of oxycodone in the clinical setting.