Buprenorphine is known as a -opioid peptide (MOP) receptor agonist, but its antinociception is compromised by the activation of nociceptin/orphanin FQ peptide (NOP) receptors in rodents. The aim of this study was to investigate the roles of MOP and NOP receptors in regulating buprenorphine-induced physiological responses in primates (rhesus monkeys). The effects of MOP antagonist (naltrexone), Over the dose range of 0.01 to 0.1 mg/kg, buprenorphine dosedependently produced antinociception, respiratory depression, and itch/scratching responses, and there was a ceiling effect at higher doses (0.1-1 mg/kg). Naltrexone (0.03 mg/kg) produced similar degrees of rightward shifts of buprenorphine's doseresponse curves for all three endpoints. Mean pK B values of naltrexone (8.1-8.3) confirmed that MOP receptors mediated mainly buprenorphine-induced antinociception, respiratory depression, and itch/scratching. In contrast, J-113397 (0.1 mg/kg) did not change buprenorphine-induced physiological responses, indicating that there were no functional NOP receptors in buprenorphine-induced effects. More importantly, both NOP agonists, Ro 64-6198 and SCH 221510, enhanced buprenorphineinduced antinociception without respiratory depression and itch/ scratching. The dose-addition analysis revealed that buprenorphine in combination with the NOP agonist synergistically produced antinociceptive effects. These findings provided functional evidence that the activation of NOP receptors did not attenuate buprenorphine-induced antinociception in primates; instead, the coactivation of MOP and NOP receptors produced synergistic antinociception without other side effects. This study strongly supports the therapeutic potential of mixed MOP/NOP agonists as innovative analgesics.

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Buprenorphine is known as a mu opioid receptor (MOP) partial agonist, but its analgesia was attenuated by activation of nociceptin/orphanin FQ peptide (NOP) receptors in rodents. The aim of this study was to investigate the roles of MOP and NOP receptors in regulating buprenorphine‐induced physiological responses in monkeys. Systemic buprenorphine (0.01–0.1 mg/kg) dose‐dependently produced antinociception, respiratory depression, and itch/scratching responses. A MOP antagonist, naltrexone 0.03 mg/kg, produced similar degrees of rightward shifts of buprenorphine's dose‐response curves for all three endpoints and confirmed that they were MOP‐mediated effects. In contrast, a NOP antagonist, J‐113397 0.1 mg/kg, did not change buprenorphine‐induced effects, indicating that there were no functional NOP receptors in buprenorphine‐induced actions. More importantly, a NOP agonist Ro 64–6198 enhanced buprenorphine‐induced antinociception, and the dose‐addition analysis revealed that systemic combination of buprenorphine and Ro 64–6198 produced superadditive antinociceptive effects. These findings provided functional evidence that co‐activation of MOP and NOP receptors produced synergistic antinociception in primates. This study strongly supports the therapeutic potential of mixed MOP/NOP agonists as innovative analgesics (Supported by USPHS grant AR‐059193).

Background: Mitochondrial dysfunction contributes to cardiac arrest induced brain injury and has been a target for neuroprotective therapies. An emerging concept suggests that hyperactivation of neuronal mitochondria following resuscitation results in hyperpolarization of the mitochondrial membrane during reperfusion, which drives generation of excess reactive oxygen species. Previous studies from our group demonstrated that limiting mitochondrial hyperactivity by non-invasively modulating mitochondrial function with specific near infrared light (NIR) wavelengths can reduce brain injury in small animal models of global and focal ischemia. Hypothesis: Inhibitory wavelengths of NIR will reduce neuronal injury and improve neurocognitive outcome in a clinically relevant swine model of cardiac arrest. Methods: Twenty-eight male and female adult swine were enrolled (3 groups: Sham, CA/CPR, and CA/CPR + NIR). Cardiac arrest (8 minutes) was induced with a ventricular pacing wire and followed by manual CPR with defibrillation and epinephrine every 30 seconds until return of spontaneous circulation (ROSC), 2 of the 20 swine that underwent CA did not achieve ROSC and were not enrolled. Treatment groups were randomized prior to arrest and blinded to the CPR team. Treatment was applied at onset of ROSC by irradiating the scalp with 750 nm and 950 nm LEDs (5W) for 2 hours. Results: Sham-operated animals all survived (8/8), whereas 22% of untreated animals subjected to cardiac arrest died within 45 min of ROSC (CA/CPR, n= 7/9). All swine treated with NIR survived the duration of the study (CA/CPR + NIR, n=9/9). Four days following cardiac arrest, neurological deficit score was improved in the NIR treatment group (50 ± 21 CA/CPR vs. 0.8 ± 0.8 CA/CPR + NIR, p < 0.05). Additionally, neuronal death in the CA1/CA3 regions of the hippocampus, assessed by counting surviving neurons with stereology, was attenuated by treatment with NIR (17917 ± 5534 neurons/mm 3 CA/CPR vs. 44655 ± 5637 neurons/mm 3 CA/CPR + NIR, p < 0.05). All data is reported as mean ± SEM. Conclusions: These data provide evidence that noninvasive modulation of mitochondria, achieved by transcranial irradiation of the brain with NIR, mitigates post-cardiac arrest brain injury.

Loss of oxygen delivery to the brain during cardiac arrest can promote significant brain injury. While prompt resuscitation is critical, the reintroduction of oxygen can potentiate injury by promoting reactive oxygen species (ROS) generation. While mitigating ROS damage may serve as a therapeutic avenue for cerebral reperfusion injury, traditional attempts to scavenge ROS have failed. This failure is thought to be due to inherent difficulties with delivery to the brain and sub-cellular targets within the early minutes of reflow. We found that specific infrared light (IRL) wavelengths penetrate the brain and reversibly reduce the activity of cytochrome c oxidase (CcO). Accordingly, we developed a non-pharmacologic therapy using specific IRL wavelengths to non-invasively modulate CcO and circumvent these delivery barriers. Our previous data shows that IRL wavelengths that reduce CcO activity also directly modulate mitochondrial respiratory rate and membrane potential, block mitochondrial ROS production, and limit neuronal death following oxygen-glucose deprivation. We hypothesized that these wavelengths could be used to inhibit ROS generation following resuscitation from cardiac arrest and thus, provide neuroprotection. IRL therapy was first evaluated for neuroprotection in the rat model of global brain ischemia (bilateral carotid occlusion and systemic hypotension - 8 minutes). Rats were randomly enrolled into IRL treatment groups, initiated immediately upon reperfusion. After 14 days, animals subjected to ischemia demonstrated an 86% loss of neurons in the CA1 hippocampus. Strikingly, for the IRL-treated animals, loss of neurons was significantly less, ranging from 17% with the best treatment to 35% with the least efficacious regimen (n=8-12, p<0.05) and preserved neurologic function, assessed by radial arm maze (n = 10, p<0.05). Finally, preliminary data from a swine model of cardiac arrest/resuscitation show a reduction in neurologic deficit score (0-150 scale 0=no deficit, 150=brain dead) with IRL treatment (Cardiac Arrest/Resuscitation = 112, Cardiac Arrest/Resuscitation + IRL treatment = 1: N = 4-6/group). These data demonstrate that IRL therapy may provide a novel strategy for the treatment of post-cardiac arrest brain injury.