Rapid shallow breathing (RSB) is mainly mediated by bronchopulmonary C-fibers (PCFs). We asked whether this RSB could be modulated by opioid. In anesthetized rats right atrial bolus injection of phenylbiguanide (PBG) to evoke RSB was repeated after: 1) intravenously giving fentanyl (μ-receptor agonist), DPDPE (δ-receptor agonist), or U-50488H (κ-receptor agonist); 2) fentanyl (iv) following naloxone methiodide, a peripheral opioid receptor antagonist; 3) bilateral microinjection of fentanyl into the nodose ganglia; 4) fentanyl (iv) with pre-blocking histamine H1 and H2 receptors by diphenhydramine and ranitidine. Systemic fentanyl challenge, but not DPDPE or U-50488H, switched the PBG-induced RSB to a long lasting apnea. This switch was blocked by naloxone methiodide rather than diphenhydramine and ranitidine. After microinjecting fentanyl into the nodose ganglia, PBG also produced an apnea. Our results suggest that activating μ-receptors is capable of turning the PCF-mediated RSB into an apnea, at least partly, via facilitating PCFs’ activity and this switching effect appears independent of the released histamine.

It is generally accepted that rapid shallow breathing (RSB) is primarily mediated by pulmonary C‐fibers (PCFs). A low dose of PCF stimulants induces RSB while a high dose produces an apnea, suggesting that the occurrence of RSB or an apnea depends on the excitatory degree of the PCFs. Because vagal nerves contain opioid receptors and PCF activity is increased by opioids, we asked if opioids would sensitize PCFs to turn the PCF‐mediated RSB into an apnea. Right atrial injection of the selective PCF stimulant phenylbiguanide (PBG) was given before and after intravenous administration of selective μ‐, δ‐, or κ‐receptor agonists (fentanyl, 6 μg/kg; DPDPE, 2 mg/kg; or U‐50488H, 4 mg/kg, respectively) in anesthetized and spontaneously breathing rats. PBG at a low dose (3–5 μg/kg) shortened the expiratory duration (TE) from 0.40 ± 0.04 s to 0.27 ± 0.05 s (P < 0.01), while it produced a long‐lasting apnea (0.52 ± 0.06 vs. 3.40 ± 0.46 s for TE, P < 0.01) after fentanyl. PBG at a high dose (10 μg/kg) also induced an apnea (2.3 ± 0.8 s) that was remarkably prolonged by fentanyl (9.1 ± 1.5 s). These facilitating effects of fentanyl were eliminated by naloxone (5 mg/kg, iv, an opioid receptor antagonist). DPDPE or U‐50488H failed to turn the PBG‐induced RSB into an apnea. This study suggests that opioids can facilitate the PCF‐mediated respiratory response through μ‐ rather than δ‐ or κ‐receptors. (Supported by ALA RT‐83131‐N)

Introduction V117957 is a recently described investigational oral, potent, and selective nociceptin/orphanin-FQ peptide (NOP) receptor partial agonist which was previously evaluated in ~200 healthy subjects. Its satisfactory safety/tolerability profile has been established with the top doses at 30mg following a single oral administration and 10mg once daily for 2 weeks. V117957 demonstrated favorable drug-like properties for insomnia treatment, including oral bioavailability, fast absorption, and rapid elimination. Methods A total of 52 patients with insomnia disorder have been evaluated in two separate randomized, double-blind, crossover, placebo-controlled sleep studies. Insomnia disorder was confirmed by screening polysomnography (PSG). All subjects received orally, for two consecutive nights, either V117957 10mg or placebo in Study #1 or 0.5, 1, 3, 6mg or placebo in Study #2. Efficacy was measured via PSG for the primary endpoint of sleep efficiency (SE) and secondary endpoints of sleep onset (latency to persistent sleep [LPS]) and maintenance (wakefulness after sleep onset [WASO]). Efficacy also was measured by patient diary (subjective sleep latency [sSL], subjective total sleep time [sTST], sWASO). Pharmacodynamics (PD) on next-day residual effects were also measured, including cognitive, psychomotor and mood effects. Results V117957 showed statistically significant greater sleep efficiency and less WASO in a dose-dependent manner (0.5-10 mg) and a statistically significant reduction in LPS at 10mg, as compared to placebo. V117957 at 0.5mg and 1mg exhibited next-day residual effects similar to placebo. At doses of 3mg or higher, V117957 showed dose-dependent next-day residual effects. V117957 was safe and well-tolerated across all doses tested with no serious adverse events, with somnolence being the most frequent treatment-emergent adverse event. No concerning laboratory findings and no clinically significant findings on vital signs and electrocardiograms have been attributed to V117957 in these subjects. Conclusion V117957 was safe and well-tolerated in patients with insomnia disorder. These results demonstrated that NOP receptors represent a novel mechanistic treatment for insomnia disorder and support continued evaluation of V117957. Support Funded by Shionogi and Imbrium Therapeutics, a subsidiary of Purdue Pharma L.P.