Sex differences in the Nociceptin/Orphanin FQ system in rat spinal cord following chronic morphine treatment
Highlights
► Chronic morphine differentially alters the N/OFQ–NOP system based on sex of the rat. ► N/OFQ levels in SC are higher in females than males, more so after chronic morphine. ► Chronic morphine reduced N/OFQ in CSF, but increased N/OFQ in the PAG of both sexes. ► Chronic morphine increased NOP receptor levels in both sexes, especially in males. ► Chronic morphine increased N/OFQ efficacy in SC of males only; no change in potency.
Introduction
Numerous studies support the existence of sex differences in the response to opioid drugs in both humans and laboratory animals. In general, females have been observed to be more sensitive to experimental pain and less sensitive to morphine analgesia (Kepler et al., 1991; Craft et al., 1999; Sarton et al., 2000; Cook and Nickerson, 2005; Ji et al., 2006; Wang et al., 2006; Dahan et al., 2008). Female and male gonadal steroids are key factors influencing sexual dimorphism in pain and analgesia (for reviews, Aloisi and Bonifazi, 2006; Dahan et al., 2008). Sex differences in the development of tolerance to morphine in rodents have been reported, though with some controversy. Some studies revealed greater morphine tolerance in male rats (Badillo-Martinez et al., 1984; Craft et al., 1999; South et al., 2001), which was challenged by other studies (Barrett et al., 2001; Holtman et al., 2004). The discrepancy between studies may be due to several factors such as means of drug administration, type of nociceptive assay utilized, hormonal status, species, and experimental design.
The NOP receptor was first cloned and identified as LC132 (Bunzow et al., 1994), opioid receptor-like 1 receptor (ORL-1; Mollereau et al., 1994), XOR1 (Chen et al., 1994), ROR-C (Fukuda et al., 1994) and KOR-3 (Pan et al., 1995). Its endogenous ligand, N/OFQ was identified within the next year by two groups. One group named it Nociceptin (Meunier et al., 1995) and the other called it Orphanin FQ (Reinscheid et al., 1995). N/OFQ exhibits a variety of complex actions; in particular, it is an important endogenous modulator of nociceptive processing (Lambert, 2008). Contrary to its anti-opioid activity at the supraspinal level (Mogil et al., 1996; Tian et al., 1997; Murphy et al., 1999; Ciccocioppo et al., 2000), N/OFQ possesses analgesic properties when administered spinally (Tian et al., 1997; King et al., 1997; Yamamoto et al., 1997). Several lines of evidence strongly suggest a role for N/OFQ in the development and maintenance of morphine tolerance at the supraspinal level. For example, intracerebroventricular (i.c.v.) injections of anti-sera directed against N/OFQ reduced analgesic tolerance associated with chronic morphine treatment (Tian and Han, 2000). Morphine tolerance was blocked in N/OFQ knock-out mice or by systemic administration of the NOP receptor antagonist J-113397 (Ueda et al., 2000; Chung et al., 2006), and intravenous administration of NOP receptor antagonist SB-612111 reversed morphine tolerance (Zaratin et al., 2004). There is a dynamic regulation of the gene itself during exposure to morphine. Pro-N/OFQ mRNA was increased in rat brain regions following both acute and chronic morphine administration (Romualdi et al., 2002). Chronic morphine treatment increased levels of N/OFQ in rat brain perfusate and in the periaqueductal gray (PAG), a region of rat brain associated with activation of the descending analgesic pathway (Yuan et al., 1999). However, it is still not clear how the production and release of endogenous N/OFQ in brain is involved in morphine tolerance, or how the development of morphine tolerance alters the pharmacological characteristics of the NOP receptor and N/OFQ.
Recent studies noted that intrathecal N/OFQ produces antinociception to acute heat, NMDA administration or mustard oil stimuli in male rats, diestrous or OVX female rats but not in proestrous or estradiol-treated OVX female rats (Claiborne et al., 2006, 2009). This supports the hypothesis that the endogenous N/OFQ–NOP system is involved in the sexual dimorphism of pain. However, it is unclear whether N/OFQ is involved in the more clinically significant problems of sex-related differences in response to chronic morphine treatment. The present study approached this question from the perspective of the spinal cord to investigate the effect of chronic morphine treatment on the N/OFQ–NOP receptor system. We provide new evidence of plastic changes of N/OFQ and NOP receptor in morphine tolerance, and confirmed that the N/OFQ system as a valuable candidate for development of new strategies for better use of existing pain medications.
Section snippets
Materials
The following drugs and materials were purchased from or provided by the sources indicated: [3H]N/OFQ and morphine HCl (Chemistry and Physiological Systems Research Branch of the National Institute on Drug Abuse, Bethesda, MD); N/OFQ RIA kit (Phoenix Pharmaceuticals, Belmont, CA).
Animals
Adult male and female Wistar rats weighing 200–250 g were provided by Charles River Labs (Wilmington, MA). Animals were housed in the animal facility under a 12-h light: 12-h dark cycle (lights on at 0600 h) with free
Sex difference in the development of chronic morphine tolerance in rats
After five consecutive days of saline or morphine (10, 20, 40, 60, 80 mg/kg, s.c., twice daily) treatment, rats of both sexes and in both treatment groups showed similar baseline TFL (Saline: Female vs. male, 2.00 ± 0.06 s vs. 1.77 ± 0.06 s; chronic morphine: Female vs. male, 2.05 ± 0.05 s vs. 1.83 ± 0.07 s), indicating that neither gender nor chronic morphine altered the basal pain threshold in this study (Fig. 1A). Tolerance to the antinociceptive actions of chronic morphine was verified by
Discussion
The morphine administration strategy in the current study successfully induced tolerance in both male and female rats. While chronic morphine treatment didn't induce TFL change in response to a saline challenge, consistent with previous reports (Bartok and Craft, 1997; Holtman et al., 2003), both male and female rats were less responsive to 10 mg/kg morphine challenge. We also found that the extent of tolerance development was significantly greater in male rats than females. Our result is in
Acknowledgments
This study was supported by grants from NIH (R01-DA017380) and the Presbyterian Health Foundation to KMS. The sponsors had no involvement in study design, analysis, collection and interpretation of the data, writing the report or in the decision to submit this paper for publication. The authors have no conflict of interest.
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