A239 COMBINED CANNABINOID RECEPTOR 1 AND MU-OPIOID RECEPTOR AGONISTS SYNERGISTICALLY INHIBIT VISCERAL PAIN <i>IN VIVO</i> WITHOUT ADVERSE SIDE EFFECTS OR TOLERANCE

Abstract Background Previously we have shown that both cannabinoid 1 receptor (CB1R) and mu-opioid receptor (MOR) agonists inhibit mechanosensitivity of colonic nociceptive nerves. However, it is unknown whether agonists of cannabinoid and opioid receptors have a synergistic interaction, such that very low doses of these agonists can be employed to reduce visceral pain and side effects. Aims To determine the effects of combined cannabinoid and opioid receptor agonists on visceral pain and its side effects. Methods Telemetric transmitters were surgically implanted into the abdominal cavity of C57/BL6 mice, with electrodes sutured to the external oblique muscle to measure the visceromotor response (VMR) to colorectal distention using a 4F arterial embolectomy catheter (volume range 20–80 µL). Mice were injected intraperitoneally with vehicle, arachidonyl-2’-chloroethylamide (ACEA), a selective CB1R agonist (0.3, 1, 3 mg/kg), HU-308, a selective CB2R agonist (0.3, 1, 3mg/kg), morphine, a MOR agonist (0.3, 3 mg/kg), or a combination, 30-minutes prior to distention. To assess side effects, pulse oximetry, heart rate, fecal pelleting, and locomotion (via an open-field maze) were measured. Data was analyzed with one or two-way ANOVA with post-hoc Bonferroni multiple comparisons test. Results ACEA dose-dependently reduced VMR (P<0.01 vs. vehicle, N=5); at the 80 µL distention, reductions of 35% (P<0.01) and 62% (P<0.01) were observed for 1 mg/kg and 3 mg/kg respectively. In contrast, HU-308 did not reduce VMR at any dose (P=0.17, N=8). Morphine (0.3 mg/kg) did not reduce VMR (P>0.99), while a higher dose (3 mg/kg) attenuated VMR (P<0.01 vs. vehicle, N=5); reductions of 32% (P<0.01) and 61% (P<0.01) at 60 and 80 µL distentions respectively. Interestingly, a combination of sub-analgesic doses of ACEA (0.3 mg/kg) and morphine (0.3 mg/kg) significantly reduced VMR (P<0.01 vs vehicle, N=5); compared to vehicle, VMR was reduced by 21% at 40 µL (P<0.05), 27% at 60 µL (P<0.01) and 60% at 80 µL (P<0.01). Chronic administration (2x/day for 6 days) of this combination did not alter the magnitude of its inhibitory effect (P=0.67, N=5), suggesting tolerance did not develop. While analgesic doses of morphine (3mg/kg) decreased oxygen saturation (P<0.01), heart rate (P<0.01) and fecal pelleting (i.e., GI motility; P<0.05), the sub-analgesic combination of ACEA and morphine had no effect (P>0.99 for all, N=5). Locomotion was unchanged by the agonists alone or combined (P=0.17). Conclusions A combination of sub-analgesic doses of CB1R and MOR agonists significantly inhibits visceral pain in vivo, without development of sides effects or tolerance with chronic use. Thus, combining low doses of CB1R and MOR agonists may be an effective visceral pain management strategy. Funding Agencies NSERC

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