DAMGO and 6beta-glycine substituted 14-O-methyloxymorphone but not morphine show peripheral, preemptive antinociception after systemic administration in a mouse visceral pain model and high intrinsic efficacy in the isolated rat vas deferens.
Peripheral micro-opioid receptors (MOR) have emerged as important components of inhibitory nociceptive pathways. Here, the antinociceptive effects of MOR agonists, the 6beta-glycine derivative of 14-O-methyloxymorphone (HS-731), DAMGO and morphine were evaluated in a mouse model of visceral pain. The abdominal acetic acid-induced writhing test was used to examine the peripheral, preemptive antinociceptive opioid action on visceral nociception. HS-731 administered subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) dose-dependently and completely inhibited writhing, being 24-598-fold more potent, depending on the administration route, than two selective MOR agonists, the enkephalin analogue [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]enkephalin (DAMGO) and morphine. A longer duration of action (2-3 h) was induced by HS-731 given before acetic acid, while shorter effect was produced by morphine (30-60 min) and DAMGO (30-45 min). The antinociceptive effects of systemic opioids were reversed by the s.c. opioid antagonist, naloxone. Blocking of central MOR by the selective MOR antagonist D-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP, i.c.v.) resulted in a significant reduction of antinociception of s.c. morphine, whereas it completely failed to antagonize the effects of systemic HS-731 or DAMGO. In in vitro studies, HS-731 and DAMGO, but not morphine showed high intrinsic efficacy, naltrexone-sensitive agonist effect at MOR of the rat vas deferens. These data demonstrate that selective activation of peripheral MOR by systemic s.c. HS-731 or DAMGO produces potent peripheral, preemptive visceral antinociception, while morphine's effects are mediated primarily through central mechanisms. Our findings support the role of peripheral MOR in the pathology of pain states involving sensitization of peripheral nociceptors.
Al-Khrasani
Mahmoud
M
Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
Spetea
Mariana
M
Friedmann
Tamas
T
Riba
Pal
P
Király
Kornel
K
Schmidhammer
Helmut
H
Furst
Susanna
S
D019342:Acetic Acid; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage*; D004852:Epoxy Compounds / Q000008:administration & dosage*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009019:Morphinans / Q000008:administration & dosage*; D009020:Morphine / Q000008:administration & dosage*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement; D010446:Peptide Fragments; D010455:Peptides / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013004:Somatostatin; D013997:Time Factors; D014649:Vas Deferens / Q000187:drug effects* / Q000502:physiology
C510434:2-((4,5alpha-epoxy-3-hydroxy-14beta-methoxy-17-methylmorphinan-6beta-yl)amino)acetic acid; D000701:Analgesics, Opioid; C529311:CTAP octapeptide; D004852:Epoxy Compounds; D009019:Morphinans; D010446:Peptide Fragments; D010455:Peptides; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D013004:Somatostatin; D009020:Morphine; D019342:Acetic Acid