Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α₂‐adrenoceptor agonists in acute pain models in mice

Abstract

1 Cannabinoid receptor agonists elicit analgesic effects in acute and chronic pain states via spinal and supraspinal pathways. We investigated whether the combination of a cannabinoid agonist with other classes of antinociceptive drugs exerted supra-additive (synergistic) or additive effects in acute pain models in mice. 2 The interactions between the cannabinoid agonist CP55,940, a 2 -adrenoceptor agonist dexmedetomidine and m-opioid receptor agonist morphine were evaluated by isobolographic analysis of antinociception in hot plate (551C) and tail flick assays in conscious male Swiss mice. Drug interactions were examined by administering fixed-ratio combinations of agonists (s.c.) in 1 : 1, 3 : 1 and 1 : 3 ratios of their respective ED 50 fractions. 3 CP55,940, dexmedetomidine and morphine all caused dose-dependent antinociception. In the hot plate and tail flick assays, ED 50 values (mg kg À1 ) were CP55,940 1.13 and 0.51, dexmedetomidine 0.066 and 0.023, and morphine 29.4 and 11.3, respectively. Synergistic interactions existed between CP55,940 and dexmedetomidine in the hot plate assay, and CP55,940 and morphine in both assays. Additive interactions were found for CP55,940 and dexmedetomidine in the tail flick assay, and dexmedetomidine and morphine in both assays. 4 Thus, an a 2 -adrenoceptor agonist or m opioid receptor agonist when combined with a cannabinoid receptor agonist showed significant synergy in antinociception in the hot plate test. However, for the tail flick nociceptive response to heat, only cannabinoid and m opioid receptor antinociceptive synergy was demonstrated. If these results translate to humans, then prudent selection of dose and receptorspecific agonists may allow an improved therapeutic separation from unwanted side effects.

Cannabinoid Receptor Type 2 Agonists Induce Transcription of the μ-Opioid Receptor Gene in Jurkat T Cells

“…Although not unequivocally established, an up-regulation of antinociceptive receptors in neurons may enhance analgetic effects, as indicated by reports investigating the role of -opioid receptors in inflammation (Brack et al, 2004) and after viral transduction into dorsal root ganglia (Xu et al, 2003). In theory, an up-regulation of -opioid receptors in neuronal cells by cannabinoids might thus contribute to synergistic effects of cannabinoids and opioids (Cichewicz and McCarthy, 2003;Yesilyurt et al, 2003;Tham et al, 2005) and to antinociceptive effects of CB2 agonists (Ibrahim et al, 2003;Hohmann et al, 2004).…”

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

“…Cannabinoid agonists may also release endogenous opioids, and a functional interplay between the endocan-ENDOCANNABINOID SYSTEM AND DISEASE nabinoid and opioid systems in modulating analgesic responses has been suggested by numerous studies (Pugh et al, 1997;Manzanares et al, 1999a,b;Houser et al, 2000;Ibrahim et al, 2005;Tham et al, 2005;Vigano et al, 2005a,b;Williams et al, 2006).…”

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

“…Importantly, evidence has been obtained through the construction of isobolograms that of the above interactions, those between R-(þ)-WIN55212 and clonidine, neostigmine or bupivicaine [73,74] as well as those between anandamide and ibuprofen [75], D 9 -THC and an opioid [81,83,86], CP55940 and dexmedetomidine [83] and CP55940 and LY235959 [90], are all synergistic rather than just additive in nature. A synergistic antinociceptive interaction has also been reported to occur between the CB 1 -selective agonist, arachidonylcyclopropylamide, and the CB 2 -selective agonist, AM1241, in a mouse model of cancer pain following intraplantar coadministration of these two compounds [22].…”