Functional consequences of short-term exposure to opioids versus cannabinoids in nonhuman primates.

Opioids provide pain relief but are associated with several adverse effects. Researchers are exploring cannabis-based medicine as an alternative. However, little is known about the tendency for physical dependence on cannabinoids in comparison with that on opioids in primates. The aim of this study was to compare the potency of heroin and delta-9-tetrahydrocannabinol (THC) in eliciting analgesic effects and the development of physical dependence between opioids and cannabinoids in both male and female rhesus monkeys. Systemic administration of either heroin (0.03-0.18 mg/kg) or THC (0.3-1.8 mg/kg) in a dose-dependent manner produced antinociceptive effects against an acute thermal nociceptive stimulus. The µ-opioid receptor antagonist naltrexone (0.01 mg/kg) and the cannabinoid receptor antagonist SR141716A (0.3 mg/kg) produced the same degree of rightward shift in the dose-response curves for heroin- and THC-induced antinociception, respectively. Monkeys implanted with telemetry devices were subjected to short-term repeated administrations (two injections per day for 1-3 days) of either heroin (0.18 mg/kg), morphine (1.8 mg/kg), THC (1.8 mg/kg), or CP 55,940 (0.032 mg/kg). Administration of naltrexone (0.01 mg/kg) increased respiration, heart rate, and blood pressure in heroin- or morphine-treated monkeys. In contrast, administration of SR141716A (0.3 mg/kg) did not cause a significant change in these physiological parameters in THC- or CP 55,940-treated monkeys. Additionally, morphine, but not CP 55,940, enhanced the monkeys' hypersensitivity to the algogen capsaicin. Collectively, these results demonstrate that in nonhuman primates, both opioids and cannabinoids exert comparable antinociception; however, physical dependence on opioids, but not cannabinoids, at their antinociceptive doses, occurs following short-term exposures.

Enhanced antidepressant-like effects of a delta opioid receptor agonist, SNC80, in rats under inflammatory pain.

Depression is a debilitating mental disorder that affects a large population worldwide. Depression and pain comorbidity is well recognized in both clinical and preclinical settings. Research studies suggest delta opioid receptor (DOR) may be involved in modulating pain as well as depression. DOR agonists produce antidepressant-like effects in animal models and their antihyperalgesic effects are enhanced in rats under inflammatory pain. However, it is unclear whether the antidepressant-like effects of DOR agonists may change in the models of pain. In this study, the antidepressant-like effects of a DOR agonist, SNC80, and a tricyclic antidepressant, amitriptyline, were compared following intracerebroventricular (i.c.v.) administration in rats under normal or inflammatory pain state elicited by injection of complete Freund's adjuvant. The forced swim test was used to determine the antidepressant-like effects. Results showed that i.c.v. SNC80 and amitriptyline dose-dependently produced antidepressant-like effects in rats under normal state. The potency of SNC80-induced antidepressant-like effects, but not amitriptyline, was enhanced in rats under inflammatory pain. This study provides functional evidence of the state-dependent effects of DOR agonists and suggests that DOR agonists may be more effective as potential antidepressants for patients experiencing both depression and pain.

Functional roles of neuromedin B and gastrin-releasing peptide in regulating itch and pain in the spinal cord of non-human primates.

Despite accumulating evidence in rodents, the functional role of neuromedin B (NMB) in regulating somatosensory systems in primate spinal cord is unknown. We aimed to compare the expression patterns of NMB and its receptor (NMBR) and the behavioral effects of intrathecal (i.t.) NMB with gastrin-releasing peptide (GRP) on itch or pain in non-human primates (NHPs). We used six adult rhesus monkeys. The mRNA or protein expressions of NMB, GRP, and their receptors were evaluated by quantitative reverse transcription polymerase chain reaction, immunohistochemistry, or in situ hybridization. We determined the behavioral effects of NMB or GRP via acute thermal nociception, capsaicin-induced thermal allodynia, and itch scratching response assays. NMB expression levels were greater than those of GRP in the dorsal root ganglia and spinal dorsal horn. Conversely, NMBR expression was significantly lower than GRP receptor (GRPR). I.t. NMB elicited only mild scratching responses, whereas GRP caused robust scratching responses. GRP- and NMB-elicited scratching responses were attenuated by GRPR (RC-3095) and NMBR (PD168368) antagonists, respectively. Moreover, i.t. NMB and GRP did not induce thermal hypersensitivity and GRPR and NMBR antagonists did not affect peripherally elicited thermal allodynia. Consistently, NMBR expression was low in both itch- and pain-responsive neurons in the spinal dorsal horn. Spinal NMB-NMBR system plays a minimal functional role in the neurotransmission of itch and pain in primates. Unlike the functional significance of the GRP-GRPR system in itch, drugs targeting the spinal NMB-NMBR system may not effectively alleviate non-NMBR-mediated itch.