Analgesic Effects and Impairment in Locomotor Activity Induced by Cannabinoid/Opioid Combinations in Rat Models of Chronic Pain.

Mohammad Alsalem,Mansour Haddad,Ahmad Altarifi,Heba Kalbouneh,Belal Azab,Khalid El-Salem,Tareq Saleh,Amer Imraish

doi:10.3390/brainsci10080523

Abstract

Both opioids and cannabinoids have well-known antinociceptive effects in different animal models of chronic pain. However, unwanted side effects limit their use. The aim of this study is to evaluate the antinociceptive effect of combining synthetic cannabinoids with subtherapeutic doses of opioids, and to evaluate the effects of these drugs/combinations on rat’s locomotor activity. Intra-plantar injection of Complete Freund’s Adjuvant (CFA) into the left hindpaw and intraperitoneal injection of streptozotocin (STZ) were used to induce inflammatory and diabetic neuropathic pain in adult male Sprague-Dawley rats, respectively. Von Frey filaments were used to assess the antinociceptive effects of opioids (morphine and tramadol) and the synthetic cannabinoids (HU210 and WIN55212) or their combinations on CFA and STZ-induced mechanical allodynia. Open field test was used to evaluate the effect of these drugs or their combinations on locomotion. HU210 and WIN55212 did not produce significant antinociceptive effect on inflammatory pain while only the maximal dose of HU210 (1 mg/kg) was effective in neuropathic pain. Only the maximal doses of morphine (3.2 mg/kg) and tramadol (10 mg/kg) had significant anti-allodynic effects in both models. Tramadol (1 mg/kg) enhanced the antinociceptive effects of WIN55212 but not HU210 in neuropathic pain with no effect on inflammatory pain. However, in open field test, the aforementioned combination did not change tramadol-induced depression of locomotion. Tramadol and WIN55212 combination produces antinociceptive effects in neuropathic but not inflammatory pain at low doses with no additional risk of locomotor impairment, which may be useful in clinical practice.

Highlights

Chronic pain is a major healthcare problem that imposes huge social and economic burden all over the world
None of the used doses of HU210 or WIN55212 induced a significant effect on the % maximal possible effect (MPE) compared to vehicle (Figure 1A,B)
Of the tested combinations used in this study, only a subtherapeutic dose of tramadol increased antinociceptive effect of WIN55212 in neuropathic pain without the antinociceptive effect of WIN55212 in neuropathic pain any further reduction in locomotion activity

Summary

Introduction

Chronic pain is a major healthcare problem that imposes huge social and economic burden all over the world. Most of the currently used analgesics such as non-steroidal anti-inflammatory drugs and opioids have limited efficacy and/or accompanied by unwanted side effects [1,2]. Considering the physiological role of cannabinoid receptors (CB1 and CB2) in controlling multiple responses including pain, cannabinoids exert analgesic effects in various models of chronic. Brain Sci. 2020, 10, 523; doi:10.3390/brainsci10080523 www.mdpi.com/journal/brainsci. Brain Sci. 2020, 10, 523 pain [3]. The wide distribution of cannabinoid and opioid receptors in the brain underpins both the therapeutic effects of cannabinoids and opioid such as analgesia, as well as their unwanted side effects such as hypomotility, nausea, sedation, constipation, respiratory depression and risk of developing tolerance and addiction [4,5]

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