Antinociceptive actions of dexmedetomidine and the kappa-opioid agonist U-50,488H against noxious thermal, mechanical and inflammatory stimuli.
The antinociceptive efficacies of both intrathecally (i.t.) and systemically administered dexmedetomidine (a selective alpha-2 adrenoceptor agonist) and U-50,488H [trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzene-acetamide] (a kappa-opioid receptor agonist) were studied during peripheral inflammation induced by carrageenan. The antinociceptive tests were the hot plate (HP), the tail flick (TF) and the paw pressure tests (PP). The motor incoordination, if any, produced by both i.t. and s.c. dexmedetomidine were evaluated with the rotarod. The interaction between dexmedetomidine and U-50,488H and between atipamezole (a selective alpha-2 adrenoceptor antagonist) and U-50,488H were also assessed. The carrageenan injection induced not only peripheral hyperalgesia but also central sensitization, as assessed by decreased PP and TF latencies, respectively. The i.t. dexmedetomidine (0.15, 0.45, 1.35, 4.05) micrograms) resulted in dose-dependent increases in the PP thresholds and TF latencies in both the control rats and the rats with unilateral inflammation, without causing changes in motor coordination, whereas on s.c. administration of dexmedetomidine (3-100 micrograms/kg), antinociception was produced in PP only at doses (30 micrograms/kg) that already interfered with rotarod performance. U-50,488H was ineffective i.t. (5-200 micrograms) but, on s.c. administration (2.5-22.5 mg/kg), dose-dependent increases were found in the PP thresholds and TF latencies of the rats with unilateral inflammation. Atipamezole, in a dose (3 mg/kg) that has been shown to block the antinociceptive effects of dexmedetomidine, did not modify the antinociceptive effects of U-50,488H.(ABSTRACT TRUNCATED AT 250 WORDS)
Idänpään-Heikkilä
J J
JJ
Department of Pharmacology and Toxicology, University of Helsinki, Finland.
Kalso
E A
EA
Seppälä
T
T
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D020926:Medetomidine; D017288:Pain Threshold / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D017473:Receptors, Opioid, kappa / Q000819:agonists*
D000316:Adrenergic alpha-Agonists; D018712:Analgesics, Non-Narcotic; D007093:Imidazoles; D011759:Pyrrolidines; D018341:Receptors, Adrenergic, alpha-2; D017473:Receptors, Opioid, kappa; C050701:atipamezole; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D020926:Medetomidine