Involvement of the nociceptin opioid peptide receptor in morphine-induced antinociception, tolerance and physical dependence in female mice

Nociceptin opioid peptide (NOP) receptor modulates pain transmission and is considered a prospective target for pain management. Under acute pain conditions in rodents, however, no definitive conclusions about effects of systemically intervening NOP receptors on nociception, classical opioid-induced antinociception, tolerance and physical dependence have been drawn. Given that opioid analgesia has sex differences, and females experience greater pain and consume more opioids, clarifying these issues in females will help develop novel analgesics. To clarify the role of NOP receptors on the pharmacological profiles of mu-opioid receptor agonists, in this study, a selective agonist (SCH221510) and antagonist (SB612111) of the NOP receptor were subcutaneously administered in female mice in multiple animal models. In hot-plate test, neither SCH221510 (3 and 10 mg/kg, sc) nor SB612111 (10 mg/kg, sc) produced significant antinociception. SCH221510 (3 mg/kg, sc) attenuated but SB612111 (10 mg/kg, sc) enhanced morphine-induced antinociception, with rightward and leftward shift of morphine dose-response curves, respectively. SCH221510 (3 mg/kg, sc) combined with morphine (10 mg/kg, sc) accelerated the development of morphine antinociceptive tolerance. Conversely, SB612111 (10 mg/kg, sc) delayed morphine tolerance development. Neither SCH221510 (3 mg/kg, sc) nor SB612111 (10 mg/kg, sc) statistically significantly altered the development of morphine-induced physical dependence. Therefore, systemic activation of NOP receptors attenuated morphine antinociception to acute thermal stimuli, facilitated morphine-induced antinociceptive tolerance but did not robustly alter physical dependence in female mice. Systemic blockade of NOP receptors produced opposite actions. These findings demonstrate that N/OFQ-NOP receptor system plays diverse roles in modulating pharmacological profiles of mu-opioid receptor agonists.