Sex differences in hyperalgesia during morphine infusion: Effect of gonadectomy and estrogen treatment
Introduction
Morphine is a widely used opiate for moderate to severe pain. However, sustained morphine delivery can paradoxically enhance pain sensitivity in humans (De Conno et al., 1991, Sjogren et al., 1998), and cause hyperalgesia in rodents (Simonnet and Rivat, 2003, Ossipov et al., 2004). Although morphine hyperalgesia is widely conceptualized as a consequence of analgesia or opioid receptor activity (Simonnet and Rivat, 2003, Ossipov et al., 2004), it is nonetheless documented after sub-analgesic morphine doses (Crain and Shen, 2001, Holtman and Wala, 2005, Juni et al., 2006) and in mice lacking all three opioid receptor genes (Juni et al., 2007). These studies indicate that morphine can directly activate distinct pain inhibitory and facilitating systems.
N-methyl-d-aspartate (NMDA) receptor antagonists attenuate hyperalgesia caused by various opioids (see reviews: Xu et al., 2003, Ossipov et al., 2004). Mechanistically, antagonists might block NMDA receptors localized to central primary afferent terminals that cause spinal sensitization and increased nociceptive input (Ossipov et al., 2004). However, NMDA antagonists also potentiate morphine analgesia (Kozela et al., 2001, Nemmani et al., 2004). Accordingly, NMDA antagonists may in fact be attenuating hyperalgesia only indirectly, by increasing the latent morphine analgesia obfuscated by – but concurrent with – increased nociception.
A critical finding is that hyperalgesia manifests during continuous morphine delivery by implanted pumps and pellets (Vanderah et al., 2001, Mao et al., 2002, Xie et al., 2005, Juni et al., 2006), indicating that morphine can directly facilitate pain. In contrast, where morphine is delivered by acute or repeated injection, there is concern that hyperalgesia may be an indirect consequence of opiate withdrawal (Gutstein, 1996, Ossipov et al., 2004). However, these studies used males exclusively, and extrapolating their findings to females may lead to erroneous conclusions for the following reasons. First, putative sex differences in nociceptive sensitivity are widely reported, and the direction of these differences and the conditions under which they are observed are unpredictable (Mogil et al., 2000). Second, males and females respond differently to chronic morphine exposure on various behavioral measures and, again, are not in a consistent direction (Craft et al., 1999, Kest et al., 2000a, Kest et al., 2000b). Finally, NMDA receptor antagonists can also cause uneven sex-related effects on morphine activity (Lipa and Kavaliers, 1990, Nemmani et al., 2004, Bryant et al., 2006), including hyperalgesia (Holtman and Wala, 2005).
To assess possible sex differences in hyperalgesia, we compared the nociceptive responses of female and male mice during continuous morphine infusion using the tail-withdrawal test. To abolish any uneven sex-related differences in analgesia concurrent with hyperalgesia, some groups were also implanted with naltrexone (NTX) pellets to provide simultaneous opioid receptor antagonism throughout the period of morphine infusion and testing. Since NMDA antagonists can potentiate morphine analgesia, their ability to reverse hyperalgesia in both sexes was also tested in mice treated simultaneously with morphine and NTX. Where sex differences were identified, the role of ovarian hormones was evaluated by testing females subject to ovariectomy (OVX), with and without subsequent estrogen replacement treatment, under identical protocols.
Section snippets
Subjects
All procedures were approved by the College of Staten Island/City University of New York Institutional Animal Care and Use Committee and conform to guidelines of the International Association for the Study of Pain. Adult male and female CD-1 mice (Charles Rivers, Kingston, NY) were maintained on a 12:12-h light/dark cycle in a climate-controlled room with free access to food and tap water. Each mouse was used once and for all groups, n ≥ 8. All surgical procedures were performed while mice were
Morphine hyperalgesia time course
Infusing 1.6 mg/kg morphine caused latency reductions from pre-morphine BL values (males: 9.1 ± 0.6, females: 8.8 ± 0.6), indicative of hyperalgesia, in placebo-pelleted mice of both sexes on Day 1 (Fig. 1A). But almost without exception, females displayed greater hyperalgesic magnitude relative to males throughout all 12 infusion days. This sex difference was particularly salient starting on Day 6, when hyperalgesia resolved in males (i.e. returned to BL latencies values) but continued unabated in
NTX-insensitive morphine hyperalgesia
Hyperalgesia has been previously demonstrated in male mice continuously infused with morphine and treated simultaneously with NTX (Juni et al., 2006). These findings are replicated here and extended to include female mice. The efficacy of NTX pellets to cause prolonged blockade of opioid receptors and morphine analgesia has been previously established (Yoburn et al., 1986, Juni et al., 2006). As evidence of their effectiveness here, NTX pellets abolished the analgesia expressed during the first
Acknowledgements
Supported by the Center for Developmental Neuroscience, College of Staten Island (AJ) and a PSC/CUNY grant (BK).
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