Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain.
BACKGROUND
Carrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates.


OBJECTIVE
The aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to non-steroidal anti-inflammatory drugs (NSAIDs).


RESULTS
Tail injection of carrageenan produced long-lasting thermal hyperalgesia in monkeys. Systemically administered agonists selective for opioid receptor subtypes, i.e., fentanyl (mu/MOP), U-50488H (kappa/KOP), SNC80 (delta/DOP) and Ro 64-6198 (nociceptin/orphanin FQ/NOP) dose-dependently attenuated carrageenan-induced thermal hyperalgesia with different potencies. In absence of carrageenan, these agonists, except SNC80, blocked acute thermal nociception. Opioid-related ligands, especially Ro 64-6198, were much more potent for their antihyperalgesic than antinociceptive effects. Both effects were mediated by the corresponding receptor mechanisms. Only fentanyl produced scratching at antihyperalgesic and antinociceptive doses consistent with its pruritic effects in humans, illustrating a translational profile of MOP agonists in nonhuman primates. Similar to SNC80, systemically administered NSAIDs ketorolac and naproxen dose-dependently attenuated carrageenan-induced hyperalgesia but not acute nociception.


CONCLUSIONS
Using two different pain modalities in nonhuman primates, effectiveness of clinically available analgesics like fentanyl, ketorolac and naproxen was distinguished and their efficacies and potencies were compared with the selective KOP, DOP, and NOP agonists. The opioid-related ligands displayed differential pharmacological properties in regulating hyperalgesia and acute nociception in the same subjects. Such preclinical primate models can be used to investigate novel analgesic agents.
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA, dsukhtan@wakehealth.edu.
Devki D
DD
Sukhtankar
Heeseung
H
Lee
Kenner C
KC
Rice
Mei-Chuan
MC
Ko
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000627:therapeutic use; D059787:Acute Pain / Q000150:complications / Q000188:drug therapy*; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use; D002351:Carrageenan; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005283:Fentanyl / Q000627:therapeutic use; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000627:therapeutic use; D007249:Inflammation / Q000150:complications / Q000188:drug therapy*; D008251:Macaca; D008297:Male; D059226:Nociceptive Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use; D011957:Receptors, Opioid / Q000819:agonists*; D013141:Spiro Compounds / Q000627:therapeutic use
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D007093:Imidazoles; D010879:Piperazines; D011957:Receptors, Opioid; C408068:Ro 64-6198; D013141:Spiro Compounds; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D002351:Carrageenan; D005283:Fentanyl