Peripheral nociceptive effects of α 2-adrenergic receptor agonists in the rat

• Published in: Neuroscience 1995-05, Vol.66 (2), p.427-432
• Main Authors: Khasar, S.G., Green, P.G., Chou, B., Levine, J.D.
• Format: Article
• Language: English
• Subjects: (±)-2-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindol; 5-Bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists - pharmacology; Adrenergic alpha-Antagonists - pharmacology; Animals; Benzazepines - pharmacology; Brimonidine Tartrate; BRL 44408; Calcimycin - pharmacology; cAMP; Clonidine - pharmacology; cyclic adenosine-3′5′-monophosphate; dimethyl sulfoxide; DMSO; Dose-Response Relationship, Drug; G-protein; guanine nucleotide-binding regulatory protein; Imidazoles - pharmacology; Indoles - pharmacology; Isoindoles; Male; norepinephrine; Norepinephrine - pharmacology; Pain Measurement; Peripheral Nervous System - drug effects; pertussis toxin, SK&F 104856, 7-chloro-2-ethenyl-3,4,5,6-tetrahydro-4-methylthieno [4,3,2-ef] benzazepine hydrochloride; PGE 2; prostaglandin E 2; PTx; Quinoxalines - pharmacology; Rats; Rats, Sprague-Dawley; UK 14,304; Yohimbine - pharmacology
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/0306-4522(94)00562-J

We have previously shown that norepinephrine can produce hyperalgesia via an α 2-adrenergic receptor mechanism. The α 2-adrenergic receptor agonist clonidine has, however, also been shown to produce peripheral analgesia. In view of the multiple α 2-subtypes currently known (i.e. α 2A, α 2Bandα 2C ), we evaluated the α 2-receptor subtypes mediating norepinephrine-induced peripheral hyperalgesia and clonidine analgesia. Norepinephrine and the α 2-adrenergic agonists clonidine and UK 14,304 (1–1000 ng), when co-injected with the calcium ionophore A23187 (1000 ng) produced dose-dependent hyperalgesia in the Randall-Selitto paw withdrawal test. Norepinephrine (100 ng) hyperalgesia was dose-dependently antagonized by α 2-adrenergic receptor antagonists. From the estimated ID 50, the rank order of potency was: SK&F 104856 ( α 2B ) ≅ imiloxan ( α 2B ) rauwolscine ( α 2C ) ≫ BRL 44408 ( α 2A ). Norepinephrine hyperalgesia was not significantly affected by pertussis-toxin treatment. Prostaglandin E 2 (100 ng) hyperalgesia was inhibited dose-dependently, by clonidine and UK 14,304. Rauwolscine was more potent in reversing the inhibitory effect of clonidine on prostaglandin E 2 than imiloxan while BRL 44408 was ineffective. The inhibitory effect of clonidine on prostaglandin E 2 hyperalgesia was reversed by pertussis toxin. These data suggest that α 2B-subtype receptors mediate (norepinephrine hyperalgesia while the antinociceptive effect of α 2-agonist is mediated by the α 2C-subtype receptor. Differential coupling of these receptor subtypes to second messenger systems and location on different cell types in the rat paw may explain, at least in part, their differential responses to α 2-agonist stimulation, leading to hyperalgesia and analgesia.