Pharmacologic evidence that spinal muscarinic analgesia is mediated by an L-arginine/nitric oxide/cyclic GMP cascade in rats.
This study was designed to determine if the antinociception produced by intrathecally (i.t.) administered muscarinic agonists in male Sprague-Dawley rats is mediated by an L-arginine/nitric oxide/cyclic GMP cascade. Seven days after implantation of intrathecal catheters, antinociception was produced with graded doses of (+)-cis-methyldioxolane (CD). The ED50 values for CD in the hot-plate and tail-flick tests were 2.6 and 2.0 nmol, respectively. The corneal and righting reflexes, as well as stepping and negative geotaxic responses, were not affected by CD. Six-minute pretreatment with 50 nmol of the nitric oxide synthase inhibitor L-NG-nitroarginine (NNR) significantly inhibited CD-produced hot-plate and tail-flick antinociception as evidenced by 6-fold shifts to the right of the CD dose-response curves. Coadministration of 150 nmol of L-arginine with NNR reversed the NNR-induced inhibition of the antinociception produced by CD. D-Arginine was without effect. Pretreatment with 500 nmol of the guanylyl cyclase inhibitor methylene blue also antagonized the antinociception produced by CD in both the hot-plate and tail-flick tests. In parallel with CD, coadministration of L-arginine with NMR reversed the NMR-induced inhibition of (+)-muscarine-produced antinociception in both nociceptive tests. Intrathecal administration of buffer, 50 nmol of NNR, 150 nmol of L- or D-arginine or 500 nmol of methylene blue, did not alter nociceptive responses when injected alone. In contrast, i.t. administration of the membrane-permeable cyclic GMP analogs, dibutyryl cyclic GMP and 8-bromo cyclic GMP, produced antinociception in both nociceptive tests when injected alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Iwamoto
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Department of Pharmacology, University of Kentucky College of Medicine, Lexington.
Marion
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D000698:Analgesia; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology*; D006152:Cyclic GMP / Q000502:physiology*; D004148:Dioxolanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007278:Injections, Spinal; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D019335:Nitroarginine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*
D004148:Dioxolanes; D018721:Muscarinic Agonists; D019335:Nitroarginine; D009569:Nitric Oxide; C024310:2-methyldioxolane; D001120:Arginine; D006152:Cyclic GMP; D008751:Methylene Blue