2.1.2. Animal Studies
Most studies indicate that male rats are less sensitive to the rewarding and reinforcing effects of heroin and other opioids than female rats (see reviews by Becker & Koob, 2016; Craft, 2008; Kokane & Perotti, 2020; Becker & Chartoff, 2019). For instance, male rats exhibit lower levels of opioid intake and take longer to acquire oral and IV opioid self-administration compared to females (Carroll et al., 2002; Cicero et al., 2003; Lacy et al., 2016; Alexander et al., 1978; Lynch & Carroll, 1999), but this effect can vary by factors such as dose, schedule of reinforcement, and level of food restriction (Mavrikaki et al., 2017). Male rats also demonstrate a morphine-induced conditioned place preference over a narrower range of doses than females (Cicero et al., 2000; Karami & Zarrindast, 2008), suggesting that male rats are less sensitive to both the reinforcing and conditioned rewarding effects of opioids.
There is some evidence that male rats may be less sensitive to the discriminative stimulus effects of mu opioids. For example, male rats acquire a morphine vs. saline discrimination at a slower rate than females, and mu opioid agonists are less potent in males than females in substitution tests (Craft et al., 1996). Male rats are more sensitive to the rate-suppressing effects of opioids than females, which can complicate interpretation of drug discrimination data due to biases in reinforcement frequency between drug and vehicle sessions between the two sexes. Indeed, when schedule parameters are changed to eliminate reinforcement bias, sex differences in the discriminative stimulus effects of opioids are no longer apparent (Craft et al., 1998a). In contrast to that seen with mu opioids, male rats are more sensitive to the discriminative stimulus effects of kappa opioids. For instance, male rats acquire a U69,593 vs. saline discrimination faster than females, and kappa agonists are more potent in males than females in substitution tests. Furthermore, unlike that seen with mu agonists, sex differences are not observed to the rate-suppressing effects of kappa agonists (Craft et al., 1998b).
Opioid-induced tolerance and physical dependence are two additional areas in which consistent sex differences are observed. Male rats develop tolerance at a faster rate (Holtman & Wala, 2005; Kasson & George, 1984; South et al., 2001) and to a greater extent (Craft et al., 1999; Barrett et al., 2001; Mousavi et al., 2007; but see Holtman et al., 2004) than females. These sex differences are mediated, in part, by gonadal hormones. For instance, gonadectomy of both males and females abolishes sex differences in the extent to which tolerance develops (Mousavi et al., 2007), and castration reduces the rate of tolerance development in males relative to both intact males and testosterone-treated females (South et al., 2001).
Sex differences in opioid-induced tolerance may be due, in part, to sex differences in sensitivity to the acute effects of opioids. Males are more sensitive to the acute antinociceptive effects of opioids, meaning that a given dose is functionally greater in males than females on a mg/kg basis (see Section 2.2.2). If males are more sensitive to a given dose of an opioid, and if that dose is functionally greater in males than in females, then tolerance will be greater at that dose in males than females (Dahan et al., 2008). Supporting this notion, male and female rats demonstrate comparable degrees of opioid-induced tolerance when functionally equivalent doses of a drug are administered chronically (Barrett et al., 2001).
Similar sex differences have been reported for opioid-induced physical dependence and withdrawal (see reviews by Craft, 2008; Becker & Koob, 2016; Bodnar & Kest, 2010). Male rodents undergoing spontaneous withdrawal from morphine exhibit greater weight loss, higher withdrawal scores, and earlier withdrawal symptoms compared to females, although the duration of withdrawal symptoms vary across species (Cicero et al., 2002a; Papelo & Contarino, 2006). Male rodents also display more severe naloxone-precipitated withdrawal symptoms than females, including greater weight loss, jumping, and wet-dog shakes (Craft et al., 1999; Diaz et al., 2001, 2005; Nayebi & Rezazadeh, 2008; Sagedhi et al., 2009; but see Cicero et al., 2002a). As noted above in regard to sex differences in opioid-induced tolerance, sex differences in opioid-induced physical dependence must take into consideration sex differences in acute opioid sensitivity, especially if the dose chosen for chronic administration is not functionally equivalent between males and females (Craft et al., 2008).