Advertisement
Research ArticleNEUROPHARMACOLOGY

Role of Steroids in Sex Differences in Morphine-Induced Analgesia: Activational and Organizational Effects

Theodore J. Cicero, Bruce Nock, Lynn O'Connor and Edward R. Meyer
Journal of Pharmacology and Experimental Therapeutics February 2002, 300 (2) 695-701; DOI: https://doi.org/10.1124/jpet.300.2.695

Abstract

The purpose of the present studies was to determine the role of either the organizational or activational sex steroids in mediating the sex differences observed in morphine-induced antinociception in the rat. To examine the organizational aspects, male pups were castrated at postnatal days 1 and 2; females were masculinized by large doses of testosterone on postnatal days 1 and 2. Adult male and female rats were also castrated over a period of 2 months to examine the role of the acute activational effects of the opiates in the already sexually differentiated adult rat brain. The results of these studies demonstrate that there were no alterations in the sex differences in opiate analgesia in castrated adult male and female rats; thus, male- and female-specific responses to opiate-induced antinociception were maintained even in the absence of the acute membrane-mediated effects of sex steroids. On the other hand, in male rats, castrated at postnatal days 1 and 2, the morphine dose-response curve shifted markedly to the right and, in fact, was almost identical to that observed in untreated females. Conversely, in female rats, masculinized by large doses of testosterone early in prenatal life, the morphine dose-response curve shifted to the left, yielding a dose-response curve that resembled that in normal males. These results strongly suggest that the sex differences that have been observed in morphine-induced analgesia are due to the organizational effects of sex steroids in the developing rat brain, rather than their acute activational effects in adulthood.

It previously has been demonstrated that there are male-female differences in the antinociceptive activity of morphine and other μ agonists in the rat (e.g., Cicero et al., 1996, 1997; Boyer et al., 1998; Craft et al., 1999; Krzanowska and Bodnar, 1999; Cook et al., 2000). Typically, male rats display a considerably greater degree of antinociception at comparable doses of morphine than do females. These differences seem to reflect intrinsic sex-related differences in the sensitivity of the brain to morphine, since it has been found that the levels of morphine in blood and brain are similar in male and female rats at comparable doses (e.g., Cicero et al., 1996, 1997; Nock et al., 1997). Sex differences are observed not only in the analgesic activity of morphine but in its discriminative stimulus properties (Craft et al., 1996,1998, 1999), the generation of physical dependence (Craft et al., 1999;Cicero et al., 2001), and its positive reinforcing properties (Alexander et al., 1978; Klein et al., 1997; Lynch and Carroll, 1999;Cicero et al., 2000).

One of the more reasonable explanations of sex-related differences in the response to opiates is that sex steroids may mediate these effects. There are two mechanisms by which sex steroids could mediate sex-based differences in the response to morphine: acute, receptor-mediated “activational” effects and long-term “organizational” effects (for reviews, see Arnold and Breedlove, 1985; Breedlove, 1992; 1994;Cooke et al., 1998). The organizational effects of steroids mediate sexual differentiation of brain morphology and neurobiology in the very late prenatal and early postnatal period in the rat. The consequence of their actions defines male and female sexually appropriate physiology and behavior, makes the brain more sensitive to the acute activational effects of the steroids during puberty, and is responsible for sexual development. In adulthood, sex steroids are necessary to maintain some typical male and female sexual and other behaviors via their acute receptor-mediated effects (i.e., their activational effects).

We are unaware of any studies that have systematically examined whether either the activational or organizational effects of sex steroids can explain the sex differences observed in the pharmacology of morphine. However, several studies have examined whether short-term castration in adult male and female rats influences the sex differences observed in the antinociceptive activity of morphine. Although in some studies, removal of steroids by castration and/or ovariectomy influenced the antinociceptive response to morphine in adult rats (e.g., Baamonde et al., 1988; Romero et al., 1988; Islam et al., 1993), the differences have been modest, often inconsistent, and many studies have failed to find any effects at all (Chatterjee et al., 1982; Bodnar et al., 1988;Kepler et al., 1989; Cicero et al., 1996). These data suggest that sex-related differences in morphine-induced antinociceptive activity may not be dependent on, or are weakly linked to, the acute receptor-mediated effects of sex steroids. Rather, it may be more reasonable to postulate that these sex-related differences are determined in large part by the organizational effects of steroids.

The purpose of the present studies was to determine the role of both the organizational and activational effects of sex steroids in mediating the sex differences observed in morphine-induced antinociception. To accomplish this goal, male pups were castrated at postnatal days 1 and 2, and females were masculinized by large doses of testosterone on postnatal days 1 and 2. This strategy was based on the now well documented observation that the introduction of androgens at critical periods during development is responsible for “masculinizing” the structural, cellular, and neuronal systems responsible for male appropriate sexual, and other sex-specific, behavior in the rat (for reviews, see Arnold and Breedlove, 1985;Breedlove, 1992; 1994; Cooke et al., 1998). In the absence of androgens, the brain develops as essentially feminine. Thus, it has been amply demonstrated that in the absence of steroids, male rats are “demasculinized” and, conversely, the introduction of steroids in females “masculinizes” the brain. Adult male and female rats were also castrated over a period of 2 months to remove circulating sex steroid levels and to examine the role of the acute activational effects of the steroids in the already sexually differentiated adult rat. Morphine-induced analgesia was assessed at 70 to 80 days of age in the pups treated postnatally and 2 to 3 months after castration in adult rats.

Experimental Procedures

Humane Care of Laboratory Animals.

All of the studies described herein were reviewed and approved by the institutional animal care and use committee, particularly with respect to the ethical standards for research on pain in conscious animals.

Materials.

Sprague-Dawley male and female rats and timed-pregnant females were purchased from Harlan Sprague Dawley Inc. (Indianapolis, IN). Morphine sulfate was generously provided by the National Institute on Drug Abuse (Rockville, MD).

Influence of Early Steroid Manipulations on Morphine-Induced Analgesia.

Following the arrival of timed-pregnant females, they were observed several times a day to determine the date of birth of the pups. At 1 and 2 days of age, the female pups were injected subcutaneously with sesame seed oil (SSO) vehicle or SSO plus testosterone propionate (1 mg in 100 μl of SSO). All the pups from a single litter were injected with either SSO or SSO + testosterone. When the pups were active (≅15 min), they were returned to their mother. At 25 to 30 days of age, the pups were weaned and housed three to a cage until they were tested as adults (>70 days).

When the male pups were 1 to 2 days of age, they were either castrated or sham-operated; all the male pups from a given litter were either castrated or sham-operated. The pups were taken from their mother and blanketed in ice. The pups were kept on a plate of glass on top of ice during surgery. When they became motionless and pale (≅15–20 min), surgery was done under a dissecting lens with a light source. A single small skin incision was made just below the abdomen with a small pair of sharp scissors. A blunt pair of forceps was then used to locate and extract the testes. The testes were removed with no cutting or ligation. If the pup was motionless, this procedure would result in little to no bleeding and no herniation. One to three small sutures with 6-0 Vicryl suture were required for closure of the incision. Once sutured, the pups were put on a maternity warming pad and allowed to recover before returning to their mothers. Warming and return to activity usually took about 30 min. The pups were active and clean of blood before being returned to their mothers. Sham-operated animals underwent the identical procedure with the obvious exception that the testes were not removed. The castrated or sham-operated pups were allowed to remain with their mother until they were 25 to 30 days old; they were then weaned and housed three to a cage until testing in adulthood (>70 days).

Castration and Ovariectomy in Adults.

To determine whether the sex-related differences we observed in morphine-induced antinociception were the result of the acute effects of steroids, groups of adult (>70 days) male and female rats were sham-operated or castrated. At least 2 months later, ED50 values for the antinociceptive activity of morphine on the hot-plate assay were determined. To confirm that castration and ovariectomy reduced sex steroids to nondetectable levels, serum levels of testosterone, estrogen, and progesterone were measured by radioimmunoassay, as described elsewhere (Cicero and Meyer, 1973; Cicero et al., 1986).

Hot-Plate Test.

Groups of male and female rats (n = 12 in each of the four groups, testosterone- or SSO-treated females and castrated or sham-operated males) were tested on a hot-plate that was set at 58°C to yield baseline (i.e., nondrug-treated) reaction times of 3 to 5 s. Four drug-free trials were used to establish baseline reaction times. The endpoint was defined as the rats licking their paws or jumping out of the cylinder (which occurred rarely); a 30-s cut-off point was used if no response occurred. The animals were then injected subcutaneously with morphine and tested every 30 min for 4 h.

Data Analysis.

To determine the ED50values in the hot-plate assays, groups of rats were injected with 3 to 5 doses of morphine falling between the ED10 and ED90. The rats were tested every 30 min for 4 h, but for the ED50 determinations, the time of the maximal antinociceptive effect (60 min) was selected. Data were expressed in terms of percentage of maximum possible effect (%MPE), defined as follows:%MPE=actual response time(s)−baseline(s)cut­off time(s)−baseline(s)×100. The area under the time-response curve was calculated by methods described elsewhere (Cicero and Meyer, 1973) to assess the magnitude of antinociception. The duration of the antinociceptive response in the hot-plate assay was defined as the time after the injection of morphine when antinociceptive activity returned to premorphine baseline levels (i.e., %MPE = 0%) and was calculated by linear regression analysis of the time-action curve for each animal; means ± S.E.M. were then calculated.

The ED50 determinations and the 95% confidence limits were determined by nonlinear regression analyses using Prism (GraphPad Software Inc., San Diego, CA). The significance of differences between the nonlinear regression models for each treatment condition were also assessed by analysis of variance (Prism; GraphPad Software Inc.).

Results

Effects of Castration or Ovariectomy on Morphine-Induced Analgesia in Adult Rats.

To illustrate the sex differences observed in morphine-induced antinociceptive activity, the morphine dose-response curves in male and female rats that were used as the sham-operated controls in the adult castration or ovariectomy studies (see below) are shown in Fig. 1. There was a substantial difference in the ED50 with males significantly more sensitive to morphine than females [8.51 mg/kg (7.57–8.94) versus 11.698 mg/kg (11.66–11.846) in males and females, respectively]. Figures 2 and 3 show the influence of castration or ovariectomy on morphine-induced analgesia in adult male and female rats, respectively. As can be seen, there were no statistically significant differences between castrated animals of either sex and those sham-operated 2 months earlier. The results shown in these figures represent the analgesic activity of subcutaneously administered morphine 60 min after its injection. No differences were observed at any interval after the injection between treated and control animals of either sex, and correspondingly, there were no differences in the total analgesia (i.e., area under the time-response curve) or duration of the analgesic response. These data, which are nearly identical to those obtained previously (Cicero et al., 1996,1997), are not repeated here.

Figure 1
Figure 1

Morphine dose-response curves in adult male and female rats that were used as sham-operated controls in subsequent studies (Figs. 2 and 3). n = 9 in each of three replications. Values are means (± S.E.M.).

Figure 2
Figure 2

Morphine dose-response curves in adult male rats ovariectomized or sham-operated 60 days prior to testing.n = 9 in each of three replications. Values are means (± S.E.M.).

Figure 3
Figure 3

Morphine dose-response curves in adult female rats castrated or sham-operated 60 days prior to testing.n = 9 in each of three replications. Values are means (± S.E.M.).

Effects of Early Castration in Males and Masculinization in Females.

Figure 4 shows the morphine dose-response curves in males, castrated or sham-operated on postnatal days 1 and 2. Figure 5 depicts results obtained in females treated with very large doses of testosterone or SSO on postnatal days 1 and 2. In contrast to the effects observed in adults, the dose-response curve in male castrates was shifted markedly to the right when compared with sham-operated controls (Fig. 4). As shown in Table 1, the resulting ED50 was substantially higher (P< 0.001) in castrated male rats than in shams. In females, masculinized in the immediate postnatal period, the morphine dose-response curve was shifted to the left, indicating that the testosterone-treated females were significantly (P < 0.05) more sensitive to morphine than SSO-treated controls; the ED50 determinations confirmed these observations (see Table 1).

Figure 4
Figure 4

Morphine dose-response curves in adult male rats (>70 days of age) that had been castrated or sham-operated on postnatal days 1 or 2. n = 9 in each of three replications. Values are means (± S.E.M.).

Figure 5
Figure 5

Morphine dose-response curves in adult female rats (>70 days of age) that had been injected with large doses of testosterone (1 mg) or SSO on postnatal days 1 or 2.n = 9 in each of three replications. Values are means (± S.E.M.).

View this table:
Table 1

The ED50 values (mg/kg) with 95% confidence limits in brackets in all treated groups and controls

Figure 6 shows the results for males and females combined. It is apparent that early castration in males moved the dose-response curve closer to that observed in SSO-treated females such that there were no significant differences between them. Conversely, the dose-response curve in masculinized females overlapped that observed in sham-operated control male rats. Analysis of variance revealed that there were significant differences in the morphine dose-response curves between males and females and treatment condition (i.e., castration and sham-surgery in males and testosterone- and SSO-treated females), see Table 2. This analysis also revealed that the dose-response curves were significantly different in all groups with the exception that there were no significant differences in the dose-response curves between sham-operated males and testosterone-treated females nor between castrated males and control females (Table 2).

Figure 6
Figure 6

Combined morphine dose-response curves in male and female rats demasculinized or masculinized, respectively, in the early postnatal period. See legends of Figs. 3 and 4 for additional details.

View this table:
Table 2

Tabular results of the analysis of variance of significant differences (P < 0.001) between all groups

Figures 7 and 8, respectively, show the time-response curve from 30 to 240 min after the injection of morphine in males and females (10 and 15 mg/kg, respectively). Results with a more extensive range of morphine doses confirmed the results shown in Figs. 7 and 8 (data not shown). Castrated male rats had significantly more total antinociception and longer durations of response than did sham-operated controls (Fig. 7). Conversely, masculinized females had much less total analgesia than SSO-treated controls (Fig. 8).

Figure 7
Figure 7

Time-action curves in adult male rats (>70 days), castrated or sham-operated in infancy, injected with morphine (10 mg/kg). The area under the time-action curve was significantly (P < 0.001) higher than in controls.

Figure 8
Figure 8

Time-action curves after morphine administration (15 mg/kg) in adult female rats (>70 days) injected with testosterone (1 mg) or SSO morphine on postnatal days 1 and 2. n = 9 in each of three replications. The area under the time-action curve was significantly (P < 0.001) higher than in controls.

Discussion

The results of these studies demonstrate that the sex differences observed in morphine-induced analgesia in the rat (e.g., Cicero et al., 1996, 1997; Boyer et al., 1998; Craft et al., 1999; Cook et al., 2000) are mediated primarily by the organizational effects of steroids in the developing rat brain as opposed to their acute activational effects in adulthood. Specifically, in agreement with previous studies (e.g.,Bodnar et al., 1988; Kepler et al., 1989; Cicero et al., 1996), there were no alterations in the sex differences observed in opiate antinociception in adult male and female rats that had been castrated to remove circulating sex steroids. Thus, male- and female-specific responses to opiate-induced antinociception were maintained even in the absence of the acute membrane-mediated effects of sex steroids. These data strongly infer that if steroids are involved in the sex differences in opiate pharmacology, these effects must have occurred during the critical postnatal differentiation of the male and female brain. Our results strongly support this inference. In male rats, castrated at postnatal days 1 and 2, the morphine dose-response curve shifted markedly to the right and, in fact, was almost identical to that observed in untreated females. Conversely, in female rats, masculinized by large doses of testosterone early in prenatal life, the morphine dose-response curve shifted to the left, yielding a dose-response curve that resembled that in normal males. These results strongly suggest that the sex differences that have been observed in morphine-induced analgesia are due primarily to the organizational effects of sex steroids, rather than their acute activational effects. Given that there are no sex differences in blood and brain levels of morphine at the time of peak analgesic effects (Cicero et al., 1996,1997; Nock et al., 1997), when strong sex differences are observed, the present results suggest that these differences are related to fundamental differences in neuronal sensitivity to morphine.

The model used in these studies to examine the role of steroids in the organizational aspects of the brain is a well established one (for reviews, see Arnold and Breedlove, 1985; Breedlove, 1992, 1994; Cooke et al., 1998). Using this model, it has been shown that the organizational structure of the rat brain is essentially feminine-like, unless testosterone surges at critical points masculinize it. Thus, testosterone and, most probably, its aromatization to estrogen determines to a substantial extent the development of the fully sexually differentiated rat brain. In the absence of testosterone, male rats are demasculinized, whereas the introduction of androgen at an early stage in females masculinizes the brain. The range of the “organizational” effects of androgens is large. Sexual dimorphisms have been observed in many regions of the brain and occur at the molecular, ultrastructural, cellular, and neural system levels. Moreover, there are both direct effects of androgens, operating through intracellular receptors, on brain organization and indirect ones generated in neural systems that interact with these androgen-sensitive systems. Our results suggest that the masculinization of the male brain can account for much if not all of the sex differences we and others have observed in opiate-induced antinociception. These data provide the most direct information to date that sex steroids are intimately involved in the neuronal sensitivity to morphine.

The nature of the differences in neuronal sensitivity to morphine is unknown. However, if one makes the logical assumption that the sex-related differences in morphine-induced antinociception observed in the present and earlier studies are in some manner due to differences in the central nervous system sensitivity to morphine, one reasonable hypothesis is that there are differences between males and females in the number or affinity of those opiate receptors involved in mediating antinociception. In this connection, Hammer (1984, 1985) has reported sex-linked differences in the number and regional distribution of opioid receptors in sexually dimorphic brain regions in males and females. Also, there is some evidence to suggest that steroids may modulate opiate receptor populations in a number of areas of brain (e.g., Hammer et al., 1994; Brown et al., 1996; Quinones-Jenab et al., 1997; Eckersell et al., 1998). Given that we have found differences in morphine-induced antinociception, which is thought to be mediated by multiple sites in the nervous system, future research should be directed toward establishing a convergence between steroid-sensitive neural systems, sex differences in opiate receptors in sexually dimorphic brain regions, and those areas thought to be involved in pain perception. In this manner, the brain regions and mechanisms that may be involved in the sex differences observed in opiate-induced antinociception may be revealed.

In prior studies, there has been some speculation that the sex differences observed in opiate antinociception could be due to more rapid metabolism of morphine in female rats resulting in somewhat lower effective brain concentrations. Although some studies have suggested that this may be at least part of the explanation (e.g., Candido et al., 1992), other experiments (Cicero et al., 1996, 1997; Nock et al., 1997) have shown no effects, and the overall differences reported, if any, have been rather small, certainly not of the magnitude to explain the large sex differences in opiate analgesia. Moreover, since the sex differences observed in opiate pharmacology are complex, with females more or less sensitive than males (see below), a biodispositional explanation seems insufficient. Thus, it seems highly unlikely that these sex differences are an artifact; rather the evidence seems clear that there are fundamental, steroid-induced differences in the sensitivity of the nervous system to morphine.

Although our results strongly indicate that the sex differences in opiate-induced antinociception are due principally to the organizational effects of the opiates occurring in the pre- and postnatal period, this conclusion should not be viewed as an absolute one. Specifically, whereas it has been shown that steroids do indeed create substantial, permanent organizational changes resulting in sexual differentiation, for some sex-specific behaviors, there is an interaction between the organizational and activational effects in the adult rat brain (for reviews, see Breedlove, 1992, 1994;Cooke et al., 1998). Our observations, that the difference between females masculinized by testosterone and controls was somewhat smaller than that observed between feminized males and controls, could suggest that at least in females, and perhaps males, the sex differences in antinociception may be influenced by both the organizational and activational effects of the steroids. This possibility needs to be directly examined by, for example, reintroducing steroids in masculinized females or demasculinized males.

The scope of sex-related differences in aspects of opiate pharmacology other than nociception is gradually being identified.Craft et al. (1996, 1998) reported that morphine served as a discriminative stimulus at lower doses in females than in males. In recently published studies, it has also been shown that there may be differences in the rewarding properties of opiates (Klein et al., 1997;Lynch and Carroll, 1999; Cicero et al., 2000). In addition, it has been shown that the expression of physical dependence is greater in males than females (Craft et al., 1999; Cicero et al., 2001). Collectively, these data seem to reflect a highly complex pattern of sex differences in the pharmacology of the opiates. In some aspects of opiate pharmacology, females seem to be more sensitive to the effects of morphine (e.g., its discriminative stimulus properties) and in others, females seem markedly less sensitive (e.g., antinociception). The mechanisms underlying these fundamental differences need to be explored. Moreover, it would be very informative to determine whether alterations in the sexual differentiation of the brain may be involved in other aspects of the sex differences observed in opiate pharmacology, other than nociception alone.

The present data raise the important issue of whether there may be sex differences in the abuse liability of opiates. Surprisingly, there is a paucity of preclinical or clinical literature in which potential differences in the abuse potential of opiates have been assessed. The absence of relatively little systematic data related to this important point is somewhat surprising, since it has been reported that, at least for alcohol and cocaine (Griffin et al., 1989; Lex, 1991; Barbor et al., 1992; Bailey et al., 1993; Ball et al., 1995;Kosten et al., 1995; Rapp et al., 1995), male and female substance abusers may differ in the severity of their abuse, may have different treatment outcomes, and/or require different prevention strategies. Whether these data reflect psychosocial or inherent biological differences between the sexes has not been examined. The present studies would seem to provide very strong evidence that these sex differences are rooted in fundamental differences in the sensitivity of the brain to morphine as opposed to other nonspecific effects of sex in opiate pharmacology (e.g., biodispositional factors). As such, additional studies designed to examine further the sex differences and the mechanisms involved seem to be essential.

Footnotes

  • Supported by Grant DA-03839 from the National Institute on Drug Abuse (to T.J.C.).

  • Abbreviations:
    SSO
    sesame seed oil
    %MPE
    maximum possible effect
    • Received September 14, 2001.
    • Accepted November 2, 2001.

References

  1. ↵
    1. Alexander BK,
    2. Coambs RB,
    3. Hadaway PF
    (1978) The effects of housing and gender on morphine self-administration in rats. Psychopharmacology 58:175–179.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Arnold AP,
    2. Breedlove SM
    (1985) Organizational and activational effects of sex steroids on brain and behavior: a reanalysis. Horm Behav 19:469–498.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Baamonde AI,
    2. Hidalgo A,
    3. Andres-Trelles F
    (1988) Sex-related differences in the effects of morphine and stress on visceral pain. Neuropharmacology 28:967–970.
  4. ↵
    1. Babor TF,
    2. Hofman M,
    3. DelBoca FK,
    4. Hesselbrock V,
    5. Meyer RE,
    6. Dolinsky ZS,
    7. Rounsaville B
    (1992) Types of alcoholics. I. Evidence for an empirically derived typology based on indicators of vulnerability and severity. Arch Gen Psychiatry 49:599–608.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Bailey PL,
    2. Rhondeau S,
    3. Schafer PG,
    4. Lu JK,
    5. Timmins BS,
    6. Foster W,
    7. Pace NL,
    8. Stanley TH
    (1993) Dose-response pharmacology of intrathecal morphine in human volunteers. Anesthesiology 79:49–59.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Ball SA,
    2. Carroll KM,
    3. Barbor TF,
    4. Rounsaville BJ
    (1995) Subtypes of cocaine abusers: support for a type A-type B distinction. J Consult Clin Psychol 63:115–124.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Bodnar RJ,
    2. Romero MT,
    3. Kramer E
    (1988) Organismic variables and pain inhibition: roles of gender and aging. Brain Res Bull 21:947–953.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Boyer JS,
    2. Morgan MM,
    3. Craft RM
    (1998) Microinjection of morphine into the rostral ventromedial medulla produces greater antinociception in male compared to female rats. Brain Res 796:315–318.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Breedlove SM
    (1992) Sexual dimorphism in the vertebrate nervous system. J Neurosci 12:4133–4142.
    OpenUrlPubMed
  10. ↵
    1. Breedlove SM
    (1994) Sexual differentiation of the human nervous system. Annu Rev Psychol 45:389–418.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Brown LL,
    2. Pasi S,
    3. Etgen AM
    (1996) Estrogen regulation of mu opioid receptor density in hypothalamic premammillary nuclei. Brain Res 742:347–351.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Candido J,
    2. Lutfy K,
    3. Billings B,
    4. Sierra V,
    5. Duttaroy A,
    6. Inturrisi CE,
    7. Yoburn BC
    (1992) Effect of adrenal and sex hormones on opioid analgesia and opioid regulation. Pharmacol Biochem Behav 42:685–692.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Chatterjee TK,
    2. Das S,
    3. Banerjee P,
    4. Ghosh JJ
    (1982) Possible physiological role of adrenal and gonadal steroids in morphine analgesia. Eur J Pharmacol 77:119–123.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Cicero TJ,
    2. Ennis T,
    3. Ogden J,
    4. Meyer ER
    (2000) Gender differences in the reinforcing properties of morphine. Pharmacol Biochem Behav 65:91–96.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Cicero TJ,
    2. Meyer ER
    (1973) Morphine pellet implantation in rats: quantitative assessment of tolerance and dependence. J Pharmacol Exp Ther 184:404–408.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Cicero TJ,
    2. Nock B,
    3. Meyer ER
    (1996) Gender-related differences in the antinociceptive properties of morphine. J Pharmacol Exp Ther 279:767–773.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Cicero TJ,
    2. Nock B,
    3. Meyer ER
    (1997) Sex-related differences in morphine's antinociceptive activity: relationship to serum and brain morphine concentrations. J Pharmacol Exp Ther 282:939–944.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Cicero TJ, Nock B, and Meyer E (2001) Sex-linked differences in the expression of physical dependence in the rat. Pharmacol Biochem Behav, in press..
  19. ↵
    1. Cicero TJ,
    2. Schmoeker PF,
    3. Meyer ER,
    4. Miller BT,
    5. Bell RD,
    6. Cytron SM,
    7. Brown CC
    (1986) Ontogeny of the opioid-mediated control of reproductive endocrinology in the male and female rat. J Pharmacol Exp Ther 236:627–633.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Cook CD,
    2. Barrett AC,
    3. Roach EL,
    4. Gowman JR,
    5. Picker MJ
    (2000) Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the mu opioid receptor. Psychopharmacology 150:430–442.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Cooke B,
    2. Hegstrom CD,
    3. Villeneuve LS,
    4. Breedlove SM
    (1998) Sexual differentiation of the vertebrate brain: principles and mechanisms. Front Neuroendocrinol 91:323–362.
  22. ↵
    1. Craft R,
    2. Heideman L,
    3. Bartok R
    (1998) Effect of gonadectomy on discriminative stimulus effects of morphine in female versus male rats. Drug Alcohol Depend 53:95–109.
    OpenUrl
  23. ↵
    1. Craft RM,
    2. Kalivas PW,
    3. Stratmann JA
    (1996) Sex differences in discriminative stimulus effects of morphine in the rat. Behav Pharmacol 7:764–778.
    OpenUrlPubMed
  24. ↵
    1. Craft RM,
    2. Stratmann JA,
    3. Bartok RE,
    4. Walpole TI,
    5. King SJ
    (1999) Sex differences in development of morphine tolerance and dependence in the rat. Psychopharmacology 143:1–7.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Eckersell CB,
    2. Popper P,
    3. Micevych PE
    (1998) Estrogen-induced alteration of mu-opioid receptor immunoreactivity in the medial preoptic nucleus and medial amygdala. J Neurosci 18:3967–3976.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Griffin ML,
    2. Weiss RD,
    3. Mirin SM,
    4. Lange U
    (1989) A comparison of male and female cocaine abusers. Arch Gen Psychiatry 46:122–128.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Hammer RP, Jr
    (1984) The sexually dimorphic region of the preoptic area in rats contains denser opiate receptor binding sites in females. Brain Res 308:172–176.
    OpenUrlCrossRefPubMed
  28. ↵
    1. Hammer RP, Jr
    (1985) The sex hormone-dependent development of opiate receptors in the rat medial preoptic area. Brain Res 360:65–74.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Hammer RP, Jr,
    2. Zhou L,
    3. Cheung S
    (1994) Gonadal steroid hormones and hypothalamic opioid circuitry. Horm Behav 28:431–437.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Islam AK,
    2. Cooper ML,
    3. Bodnar RJ
    (1993) Interactions among aging, gender and gonadectomy effects upon morphine antinociception in rats. Physiol Behav 54:45–53.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Kepler KL,
    2. Kest B,
    3. Kiefel JM,
    4. Cooper ML,
    5. Bodnar RJ
    (1989) Roles of gender, gonadectomy and estrous phase in the analgesic effects of intracerebroventricular morphine in rats. Pharmacol Biochem Behav 34:119–127.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Klein LC,
    2. Popke JE,
    3. Grunberg NE
    (1997) Sex differences in effects of predictable and unpredictable footshock on fentanyl self-administration in rats. Exp Clin Psychopharmacol 5:99–106.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Kosten TA,
    2. Rounsaville BJ,
    3. Kosten TR
    (1995) Gender differences in cocaine use and treatment. Am Psych Assoc Annu Mtg, ; Abstract 28D, APA Press, Washington, DC..
  34. ↵
    1. Krzanowska EK,
    2. Bodnar RJ
    (1999) Morphine antinociception elicited from the ventrolateral periaqueductal gray is sensitive to sex and gonadectomy differences in rats. Brain Res 821:224–230.
    OpenUrlCrossRefPubMed
  35. ↵
    1. Lex BW
    (1991) Some gender differences in alcohol and polysubstance users. Health Psychol 10:121–132.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Lynch WJ,
    2. Carroll ME
    (1999) Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology 144:77–82.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Nock B,
    2. Wich M,
    3. Cicero TJ
    (1997) Chronic exposure to morphine increases corticosteroid-binding globulin. J Pharmacol Exp Ther 282:1262–1268.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Quinones-Jenab V,
    2. Jenab S,
    3. Ogawa S,
    4. Inturrisi C,
    5. Pfaff DW
    (1997) Estrogen regulation of mu-opioid receptor mRNA in the forebrain of female rats. Brain Res Mol Brain Res 47:134–138.
    OpenUrlPubMed
  39. ↵
    1. Rapp SE,
    2. Ready LB,
    3. Nessly ML
    (1995) Acute pain management in patients with prior opioid consumption: a case-controlled retrospective review. Pain 61:195–201.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Romero JT,
    2. Cooper ML,
    3. Komisarusk BR,
    4. Bodnar RJ
    (1988) Gender-specific and gonadectomy-specific effects upon swim analgesia: role of steroid replacement therapy. Physiol Behav 44:257–265.
    OpenUrlCrossRefPubMed
Back to top

In this issue

Download PDF
Article Alerts
Email Article
Citation Tools

Research ArticleNEUROPHARMACOLOGY

Role of Steroids in Sex Differences in Morphine-Induced Analgesia: Activational and Organizational Effects

Theodore J. Cicero, Bruce Nock, Lynn O'Connor and Edward R. Meyer
Journal of Pharmacology and Experimental Therapeutics February 1, 2002, 300 (2) 695-701; DOI: https://doi.org/10.1124/jpet.300.2.695
Reddit logo Twitter logo Facebook logo Mendeley logo

Jump to section

Advertisement