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 µ-
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 µ-
opioid receptor agonists.