ro-64-6198 and Pain

Although mu opioid (MOP) receptor agonists are the most commonly used analgesics for the treatment of moderate to severe pain in the clinic, the side effects of MOP agonists such as abuse liability limit their value as a medication. Research to identify novel analgesics without adverse effects is pivotal to advance the health care of humans. The nociceptin/orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, mediates distinctive actions in nonhuman primates which suggests the possibility that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects associated with MOP agonists. The present review highlights the recent progress of pharmacological studies of NOP-related ligands in primates. Selective NOP agonists, either peptidic or nonpeptidic, produce full analgesia in various assays in primates, when delivered systemically or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers, indicating a lack of abuse liability. Given that NOP agonists have low abuse liability and that coactivation of NOP and MOP receptors produces synergistic antinociception, it is worth developing bifunctional NOP/MOP ligands. The outcomes of these studies and recent developments provide new perspectives to establish a translational bridge for understanding the biobehavioral functions of NOP receptors in primates and for facilitating the development of NOP-related ligands as a new generation of analgesics without abuse liability in humans.

Topics: Analgesics; Analgesics, Opioid; Animals; Azabicyclo Compounds; Imidazoles; Macaca; Nociceptin Receptor; Pain; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spiro Compounds; Substance-Related Disorders

The NOP receptor (formerly referred to as opiate receptor-like 1, ORL-1, LC132, OP(4), or NOP(1)) is a G protein-coupled receptor that shares high homology to the classic opioid MOP, DOP, and KOP (mu, delta, and kappa, respectively) receptors and was first cloned in 1994 by several groups. The NOP receptor remained an orphan receptor until 1995, when the endogenous neuropeptide agonist, known as nociceptin or orphanin FQ (N/OFQ) was isolated. Five years later, a group at Hoffmann-La Roche reported on the selective, nonpeptide NOP agonist Ro 64-6198, which became the most extensively published nonpeptide NOP agonist and a valuable pharmacological tool in determining the potential of the NOP receptor as a therapeutic target. Ro 64-6198 is systemically active and achieves high brain penetration. It has subnanomolar affinity for the NOP receptor and is at least 100 times more selective for the NOP receptor over the classic opioid receptors. Ro 64-6198 ranges from partial to full agonist, depending on the assay. Preclinical data indicate that Ro 64-6198 may have broad clinical uses, such as in treating stress and anxiety, addiction, neuropathic pain, cough, and anorexia. This review summarizes the pharmacology and preclinical data of Ro 64-6198.

Topics: Animals; Anxiety; Drug Evaluation, Preclinical; Humans; Imidazoles; Nociceptin Receptor; Pain; Receptors, Opioid; Spiro Compounds; Stress, Physiological

Mu-opioid receptor agonists are clinically effective analgesics, but also produce undesirable effects that limit their clinical utility. The nociceptin opioid peptide (NOP) receptor system also modulates nociception, and NOP agonists might be useful adjuncts to enhance the analgesic effects or attenuate the undesirable effects of mu-opioid agonists. The present study determined behavioral interactions between the NOP agonist (-)-Ro 64-6198 and mu-opioid ligands that vary in mu-opioid receptor efficacy (17-cyclopropylmethyl-3,14β-dihyroxy-4,5α-epoxy-6α-[(3 ́-isoquinolyl)acetamindo]morphinan (NAQ) < buprenorphine < nalbuphine < morphine = oxycodone < methadone) in male rhesus monkeys. For comparison, Ro 64-6198 interactions were also examined with the kappa-opioid receptor agonist nalfurafine. Each opioid ligand was examined alone and following fixed-dose Ro 64-6198 pretreatments in assays of thermal nociception (n = 3-4) and schedule-controlled responding (n = 3). Ro 64-6198 alone failed to produce significant antinociception up to doses (0.32 mg/kg, IM) that significantly decreased rates of responding. All opioid ligands, except NAQ and nalfurafine, produced dose- and thermal intensity-dependent antinociception. Ro 64-6198 enhanced the antinociceptive potency of buprenorphine, nalbuphine, methadone, and nalfurafine. Ro 64-6198 enhancement of nalbuphine antinociception was NOP antagonist SB-612111 reversible and occurred under a narrow range of dose and time conditions. All opioid ligands, except NAQ and buprenorphine, produced dose-dependent decreases in rates of responding. Ro 64-6198 did not significantly alter mu-opioid ligand rate-decreasing effects. Although these results suggest that NOP agonists may selectively enhance the antinociceptive vs. rate-suppressant effects of some mu-opioid agonists, this small enhancement occurred under a narrow range of conditions dampening enthusiasm for NOP agonists as candidate "opioid-sparing" adjuncts.

Topics: Analgesics, Opioid; Animals; Imidazoles; Macaca mulatta; Male; Opioid Peptides; Pain; Receptors, Opioid; Spiro Compounds

Behavioral effects of a nonpeptidic NOP (nociceptin/orphanin FQ Peptide) receptor agonist, Ro 64-6198, have not been studied in primate species. The aim of the study was to verify the receptor mechanism underlying the behavioral effects of Ro 64-6198 and to systematically compare behavioral effects of Ro 64-6198 with those of a mu-opioid receptor agonist, alfentanil, in monkeys. Both Ro 64-6198 (0.001-0.06 mg/kg, s.c.) and alfentanil (0.001-0.06 mg/kg, s.c.) produced antinociception against an acute noxious stimulus (50 degrees C water) and capsaicin-induced allodynia. An NOP receptor antagonist, J-113397 (0.01-0.1 mg/kg, s.c.), dose-dependently produced rightward shifts of the dose-response curve of Ro 64-6198-induced antinociception. The apparent pA(2) value of J-113397 was 8.0. Antagonist studies using J-113397 and naltrexone revealed that Ro 64-6198 produced NOP receptor-mediated antinociception independent of mu-opioid receptors. In addition, alfentanil dose-dependently produced respiratory depression and itch/scratching responses, but antinociceptive doses of Ro 64-6198 did not produce such effects. More important, Ro 64-6198 did not produce reinforcing effects comparable with those of alfentanil, cocaine, or methohexital under self-administration procedures in monkeys. These results provide the first functional evidence that the activation of NOP receptors produces antinociception without reinforcing effects in primates. Non-peptidic NOP receptor agonists may have therapeutic value as novel analgesics without abuse liability in humans.

Topics: Alfentanil; Analgesics, Opioid; Animals; Behavior, Animal; Benzimidazoles; Capsaicin; Central Nervous System Agents; Dose-Response Relationship, Drug; Female; Hot Temperature; Imidazoles; Macaca mulatta; Male; Naltrexone; Narcotic Antagonists; Nociceptin Receptor; Pain; Piperidines; Pruritus; Receptors, Opioid; Receptors, Opioid, mu; Reinforcement, Psychology; Respiratory Insufficiency; Spiro Compounds

The aim of the present study was to clarify the role of nociceptin system in pain modulation. The effects of the synthetic nociceptin (NOP) receptor agonist, Ro64-6198 ((1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one), on reactivity to acute noxious stimuli were assessed in C57BL/6N (B6) mice in tail-flick, hot-plate and shock threshold tests. The mu receptor agonist, morphine, was used in each study for comparison. In the tail-flick test, morphine (4 and 8 mg/kg, i.p.) produced analgesia, while Ro64-6198 (0.3, 1 and 3 mg/kg, i.p.) increased pain sensitivity. The effects of Ro64-6198 were seen in naïve but not in mice previously habituated to testing conditions, indicating that increased pain sensitivity may be due to inhibition of stress-induced analgesia. In the hot-plate and the shock threshold tests, Ro64-6198 produced analgesia in B6 mice, like morphine. These effects were reproduced in wild-type but not in NOP receptor knockout mice. Finally, when injected conjointly at subthreshold doses, Ro64-6198 (1 mg/kg) and morphine (1 mg/kg) acted in additive manner to reduce pain sensitivity in the hot-plate test. Together these results show that systemic activation of NOP receptors produced bidirectional changes in pain sensitivity depending on the experimental conditions. They also suggest that central NOP and mu receptors may inhibit reactivity to acute noxious stimuli via independent neural mechanisms.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Synergism; Hot Temperature; Imidazoles; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Nociceptin Receptor; Pain; Pain Measurement; Pain Threshold; Reaction Time; Receptors, Opioid; Receptors, Opioid, mu; Spiro Compounds; Stress, Physiological; Tail

The biochemical and behavioral effects of a nonpeptidic, selective, and brain-penetrant agonist at the ORL1 receptor are reported herein. This low molecular weight compound [(1S,3aS)-8- (2,3,3a,4,5, 6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza- spiro[4. 5]decan-4-one] has high affinity for recombinant human ORL1 receptors and has 100-fold selectivity for ORL1 over other members of the opioid receptor family. It is a full agonist at these receptors and elicits dose-dependent anxiolytic-like effects in a set of validated models of distinct types of anxiety states in the rat (i.e., elevated plus-maze, fear-potentiated startle, and operant conflict). When given systemically, the compound has an efficacy and potency comparable to those of a benzodiazepine anxiolytic such as alprazolam or diazepam. However, this compound is differentiated from a classical benzodiazepine anxiolytic by a lack of efficient anti-panic-like activity, absence of anticonvulsant properties, and lack of effects on motor performance and cognitive function at anxiolytic doses (0.3 to 3 mg/kg i.p.). No significant change in intracranial self-stimulation performance and pain reactivity was observed in this dose range. Higher doses of this compound (>/=10 mg/kg) induced disruption in rat behavior. These data confirm the notable anxiolytic-like effects observed at low doses with the orphanin FQ/nociceptin neuropeptide given locally into the brain and support a role for orphanin FQ/nociceptin in adaptive behavioral fear responses to stress.

Topics: Acoustic Stimulation; Alprazolam; Animals; Anti-Anxiety Agents; Cognition; Conflict, Psychological; Diazepam; Dose-Response Relationship, Drug; Electroshock; Epilepsy; Fear; Humans; Imidazoles; Male; Maze Learning; Nociceptin Receptor; Pain; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Recombinant Proteins; Reflex, Startle; Seizures; Self Stimulation; Spiro Compounds