A comparison of the antinociceptive and adverse effects of the mu-opioid agonist morphine and the delta-opioid agonist SNC80.
delta-Opioid receptor agonists have been postulated to induce analgesia without the adverse effects commonly associated with mu-opioids e.g. morphine. In the present study, we evaluated the occurrence of antinociceptive and opioid-like side effects in rats (n=5-7) treated with a single dose of subcutaneous morphine (0.01 to 40 mg/kg) or SNC80 (0.63 to 80 mg/kg). The antinociceptive effects of morphine and SNC80 were compared using a range of nociceptive tests including the tail withdrawal test, the acetic acid-induced abdominal constriction (writhing) assay, the automated formalin test and a model of inflammation-induced thermal hyperalgesia. The adverse effects of both drugs were examined in animal models for gastrointestinal (GI) inhibition (charcoal test; ricinus oil test), respiratory depression (blood-gas analysis), motor disturbances (automated rotarod model) and abuse liability (drug discrimination learning). Morphine displayed significant antinociceptive and adverse effects in all the animal models employed. SNC80 exhibited a significant effect in the writhing test and limited efficacy in a model of inflammation-induced thermal hypersensitivity. A delay in the occurrence of diarrhoea and some limited increases in PCO(2) were observed with the higher doses of SNC80 (> or =40 mg/kg). In conclusion, the delta-opioid agonist SNC80 lacks both the analgesic efficacy and adverse effects of mu-opioids. However, the activity of SNC80 in the inflammatory model suggests delta-opioid agonists may be useful analgesics in the treatment of some forms of inflammatory pain.
Gallantine
Elizabeth L
EL
CNS Discovery Research, Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium. egallant@prd-be.jnj.com
Meert
Theo F
TF
D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000633:toxicity; D002245:Carbon Dioxide / Q000097:blood; D004193:Discrimination Learning / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D009020:Morphine / Q000494:pharmacology* / Q000633:toxicity; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*
D001549:Benzamides; D010879:Piperazines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D002245:Carbon Dioxide; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D009020:Morphine