Antinociceptive effects of delta-opioid agonists in Rhesus monkeys: effects on chemically induced thermal hypersensitivity.
The effects of SNC80 and other structurally related delta-opioid receptor agonists were assessed under conditions of chemically induced hypersensitivity to thermal stimuli in four rhesus monkeys. The shaved tail of each monkey was exposed to warm water (38, 42, 46, and 50 degrees C), and the tail-withdrawal latency from each temperature was recorded. The effects of drugs on the temperature that produced a 10-s tail-withdrawal latency (the T(10) value) were examined. Capsaicin (0.01-0.32 mg) injected into the tail of monkeys dose dependently decreased the T(10), indicating that capsaicin increased sensitivity to thermal stimuli. A dose of 0.1 mg of capsaicin decreased the T(10) from 48.0 to 42.1 degrees C (a -5.9 degrees C change) 15 min after injection. SNC80 (1.0-10.0 mg/kg s.c.) dose dependently blocked the capsaicin-induced decrease in the T(10), and 10.0 mg/kg SNC80 fully blocked the effects of capsaicin. The delta-selective antagonist naltrindole (0.1-1.0 mg/kg) dose dependently antagonized the effects of SNC80, whereas a mu-selective dose of the opioid antagonist quadazocine (0.1 mg/kg) did not. Two other delta-selective agonists, SNC162 (1.0-10.0 mg/kg) and SNC243A (1.0-10.0 mg/kg), also dose dependently blocked capsaicin-induced thermal hypersensitivity. In contrast, neither SNC67 (10.0 mg/kg), which is the (-)-enantiomer of SNC80, nor the nonsteroidal anti-inflammatory drug (NSAID) ketorolac (1.0-10.0 mg/kg) modified the effects of capsaicin. SNC80 was also effective in reversing thermal hypersensitivity induced by prostaglandin E(2) (0.0158 mg) and Freund's complete adjuvant (10% concentration). These findings suggest that delta-agonists have antinociceptive effects in primates under conditions of chemically induced thermal hypersensitivity and might be effective under a broader range of conditions than clinically available NSAIDs.
Brandt
M R
MR
Alcohol and Drug Abuse Research Center, Harvard Medical School-McLean Hospital, Belmont, Massachusetts, USA. brandtm@war.wyeth.com
Furness
M S
MS
Mello
N K
NK
Rice
K C
KC
Negus
S S
SS
D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D002211:Capsaicin; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005620:Freund's Adjuvant / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control*; D020910:Ketorolac / Q000009:adverse effects / Q000627:therapeutic use; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000009:adverse effects / Q000627:therapeutic use; D010146:Pain / Q000517:prevention & control*; D010147:Pain Measurement; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D017465:Receptors, Opioid, delta / Q000819:agonists*
D000700:Analgesics; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D010879:Piperazines; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D009020:Morphine; D005620:Freund's Adjuvant; D015232:Dinoprostone; D002211:Capsaicin; D020910:Ketorolac