Non-cannabinoid CB1, non-cannabinoid CB2 antinociceptive effects of several novel compounds in the PPQ stretch test in mice.
The analgesic and anti-hyperalgesic effects of cannabinoid- and vanilloid-like compounds, plus the fatty acid amide hydrolase (FAAH) inhibitor Cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597), and acetaminophen, were evaluated in the phenyl-p-quinone (PPQ) pain model, using different routes of administration in combination with opioid and cannabinoid receptor antagonists. All the compounds tested produced analgesic effects. Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide ((R)-methanandamide) were active by three routes of administration: i.p., s.c. and, p.o. Delta(9)-THC produced ED(50)s of 2.2 mg/kg (0.3-15.6) i.p., 9 mg/kg (4.3-18.9) s.c., and 6.4 mg/kg (5.5-7.6) p.o. Similarly, (R)-methanandamide yielded ED(50)s of 2.9 mg/kg (1-8) i.p., 11 mg/kg (7-17) s.c., and 11 mg/kg (0.9-134) p.o. N-vanillyl-arachidonyl-amide (arvanil) was active by two routes, producing ED(50)s of 4.7 mg/kg (3.0-7.4) s.c. and 0.06 mg/kg (0.02-0.2) i.p. Palmitoylethanolamide, URB597, and acetaminophen were active i.p., resulting in ED(50)s of 3.7 mg/kg (3.2-4.2), 22.9 mg/kg (11.1-47.2), and 160 mg/kg (63-405), respectively. None of the cannabinoid or opioid receptor antagonists tested blocked the compounds evaluated, with two exceptions: the antinociceptive effects of Delta(9)-THC and URB597 were completely blocked by SR141716A, a cannabinoid CB(1) receptor antagonist. Western immunoassays performed using three opioid receptor antibodies, a cannabinoid CB(1) receptor antibody and a transient receptor potential vanilloid type 1(TRPV(1)) receptor antibody, yielded no change in receptor protein levels after short-term arvanil, (R)-methanandamide or Delta(9)-THC administration. These data suggest that all the compounds tested, except Delta(9)-THC and URB597, produced analgesia via a non-cannabinoid CB(1), non-cannabinoid CB(2) pain pathway not yet identified.
Haller
Victoria L
VL
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, USA.
Cichewicz
Diana L
DL
Welch
Sandra P
SP
D000082:Acetaminophen / Q000494:pharmacology; D000577:Amides; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D016227:Benzoquinones; D001892:Camphanes / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D004983:Ethanolamines; D006930:Hyperalgesia / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008636:Mesencephalon / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D010169:Palmitic Acids / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects* / Q000378:metabolism; D011957:Receptors, Opioid / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D000077285:Rimonabant; D013116:Spinal Cord / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000032:analysis / Q000187:drug effects / Q000378:metabolism
D000577:Amides; D000700:Analgesics; D001095:Arachidonic Acids; D001549:Benzamides; D016227:Benzoquinones; D001892:Camphanes; D002219:Carbamates; D063388:Endocannabinoids; D004983:Ethanolamines; D009292:Narcotic Antagonists; D010169:Palmitic Acids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011957:Receptors, Opioid; C110630:SR 144528; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C121153:arvanil; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C088155:methanandamide; D000082:Acetaminophen; C029322:phenylbenzoquinone; C005958:palmidrol; D013759:Dronabinol; D000077285:Rimonabant; D002211:Capsaicin