Characterization of the Discriminative Stimulus Effects of a NOP Receptor Agonist Ro 64-6198 in Rhesus Monkeys

Abstract

Nociceptin/orphanin FQ receptor (NOP) agonists have been reported to produce antinociceptive effects in rhesus monkeys with comparable efficacy to m-opioid receptor (MOP) agonists, but without their limiting side effects. There are also known to be species differences between rodents and nonhuman primates (NHPs) in the behavioral effects of NOP agonists. The aims of this study were the following: 1) to determine if the NOP agonist Ro 64-6198 could be trained as a discriminative stimulus; 2) to evaluate its pharmacological selectivity as a discriminative stimulus; and 3) to establish the order of potency with which Ro 64-6198 produces discriminative stimulus effects compared with analgesic effects in NHPs. Two groups of rhesus monkeys were trained to discriminate either fentanyl or Ro 64-6198 from vehicle. Four monkeys were trained in the warmwater tail-withdrawal procedure to measure antinociception. Ro 64-6198 produced discriminative stimulus effects that were blocked by the NOP antagonist J-113397 and not by naltrexone. The discriminative stimulus effects of Ro 64-6198 partially generalized to diazepam, but not to fentanyl, SNC 80, ketocyclazocine, buprenorphine, phencyclidine, or chlorpromazine. Fentanyl produced stimulus effects that were blocked by naltrexone and not by J-113397, and Ro 64-6198 did not produce fentanyl-appropriate responding in fentanyltrained animals. In measures of antinociception, fentanyl, but not Ro 64-6198, produced dose-dependent increases in tailwithdrawal latency. Together, these results demonstrate that Ro 64-6198 produced stimulus effects in monkeys that are distinct from other opioid receptor agonists, but may be somewhat similar to diazepam. In contrast to previous findings, Ro 64-6198 did not produce antinociception in the majority of animals tested even at doses considerably greater than those that produced discriminative stimulus effects.

Role of mu-opioid agonist efficacy on antinociceptive interactions between mu agonists and the nociceptin opioid peptide agonist Ro 64-6198 in rhesus monkeys

“…Buprenorphine also failed to significantly alter rates of responding and these results were consistent with previous buprenorphine results in male monkeys (Negus et al, 2002). Ro 64-6198 rate-decreasing effects in the present study were consistent with previous Ro 64-6198 results in drug discrimination (Saccone et al, 2016) and extended previous findings by determining Ro 64-6198 time course and sensitivity to SB-612111antagonism. Overall, the behavioral effects of the mu-opioid ligands and nalfurafine alone in the present study provide an empirical foundation for examining interactions with Ro 64-6198.…”

“…The NOP agonist Ro 64-6198 also did not produce antinociception up to doses that significantly decreased rates of responding. These results were consistent with a previous monkey study (Saccone et al, 2016), but inconsistent with other monkey studies (Cremeans et al, 2012;Podlesnik et al, 2011). Reasons for the inconsistent NOP agonist antinociceptive effects in monkeys are not entirely clear and highlight the importance of evaluating candidate analgesics across a broad range of experimental conditions.…”

Utility of Nonhuman Primates in Substance Use Disorders Research

“…Nonhuman primates have also demonstrated utility as research subjects for the evaluation of novel psychoactive substances targeting other receptor systems, such as the opioid or cannabinoid systems. For example, nonhuman primates have served as research subjects evaluating the behavioral effects of novel mu-opioid agonists, such as fentanyl derivatives (France et al 1995), and novel nonopioid compounds, such as nociceptin/orphanin FQ agonists (Ding et al 2016;Ko et al 2009;Saccone et al 2016). Regarding the cannabinoid system, squirrel monkeys are the only species of research animal for which Δ9-tetrahydrocannabinol and other novel cannabinoid compounds are robustly self-administered (Justinova et al 2003;Justinová et al 2011;Schindler et al 2016).…”

Analysis of the distribution of spinal NOP receptors in a chronic pain model using NOP‐eGFP knock‐in mice

“…When administered systemically, AT‐202 blocks morphine analgesia (Ozawa et al, ). In non‐human primates, the effect of systemic administration of Ro 64‐6198 is unclear as one report demonstrated potent antinociceptive activity (Ko et al, ) while a second report found systemic administration of Ro 64‐6198 to be ineffective under similar conditions (Saccone et al, ). For chronic pain, the situation is different as systemic administration of NOP receptor agonists can block mechanical allodynia in various chronic and inflammatory pain models (Khroyan et al, ).…”