Effects and Side Effects of Cannabinoid/Opioid Combination in a Chronic Pain Model in Rats

Abstract

Chronic pain is considered a growing healthcare problem becoming a major cause of global burden. Prolonged use of the currently used analgesics such opioids is associated with adverse effects; urging the need for safer alternatives. Cannabinoids are a group of compounds structurally related to Δ9‐tetrahydrocannabinol (Δ9‐THC). Both cannabinoids and opioids produce antinociception in different chronic pain animal models. However, therapeutic doses of these drugs may be accompanied by undesirable side effects, such as abuse liability and decrease locomotion in animals. The aim of this study was to assess the outcomes of combining range of doses of opioids and cannabinoids that are sufficient to produce antinociception without producing unwanted side effects. Inflammatory pain was induced by intra‐plantar injection of Complete Freund's Adjuvant (CFA) into the left hindpaw of adult male Sprague Dawley rats. Von Frey filaments were applied to the mid‐plantar aspect of the left hind paw using the “up‐down” method to determine the CFA‐induced mechanical allodynia. Antinociceptive effect of morphine (0.32, 1 and 3.2 mg/kg; i.p), the synthetic cannabinoid CP55940 (0.032, 0.1 and 0.32 mg/kg; s.c.), their combinations, or their vehicles was evaluated 3–9 day post‐CFA administration. Intracranial self‐stimulation (ICSS) test was utilized to evaluate the abuse liability of these drugs or their combinations. Morphine produced significant antinociceptive effects at 1 and 3.2 mg/kg, but not at the lowest dose of 0.32 mg/kg with minimal changes in ICSS. CP55940 showed significant antinociceptive effects only at the highest administered dose (0.32 mg/kg), while producing depression in ICSS at 0.1 and 0.32 mg/kg. The sub‐theraputic dose of morphine (0.32 mg/kg) was co‐administered with the different doses of CP55940 (0.032, 0.1 and 0.32 mg/kg). 0.32 mg/kg morphine enhanced the antinocicpetive effects of CP55940, such that CP55940 produced antinociception at lower dose (0.1 mg/kg) compared to vehicle. However, in ICSS test, the aforementioned combinations did not change CP55940‐induced depression of ICSS. In conclusion morphine and CP55940 produce analgesic effects at lower doses if combined together with no additional risk of abuse liability side effects, which may be useful in clinical practice.Support or Funding InformationScientific Research Support Fund (MPH/1/29/2016)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.