Noradrenaline activates the NO/cGMP/ATP-sensitive K+ channels pathway to induce peripheral antinociception in rats

• Published in: Nitric oxide 2012-03, Vol.26 (3), p.157-161
• Main Authors: Romero, Thiago R.L., Guzzo, Luciana S., Perez, Andrea C., Klein, André, Duarte, Igor D.G.
• Format: Article
• Language: English
• Subjects: Analgesics - pharmacology; Analysis of Variance; Animals; Cyclic GMP - metabolism; Foot - physiology; K+ channels; KATP Channels - agonists; KATP Channels - metabolism; Male; Nitric oxide; Nitric Oxide - metabolism; Nociception - drug effects; Nociception - physiology; Noradrenaline; Norepinephrine - pharmacology; Pain Measurement; Peripheral antinociception; Pressure; Rats; Rats, Wistar
• ISSN: 1089-8603; 1089-8611
• DOI: 10.1016/j.niox.2012.01.006

► It was investigated the involvement of NO/cGMP/KATP in NA-induced antinociception. ► The rat paw PGE2-induced hyperalgesia and pressure test was used. ► l-NOarg and glibenclamide antagonized the antinociception effect induced by NA. ► ODQ antagonized and zaprinast potentiated the NA-induced antinociception. ► NA induces peripheral antinociceptive effect by activation of NO/cGMP/KATP pathway. Despite the classical peripheral pronociceptive effect of noradrenaline (NA), recently studies showed the involvement of NA in antinociceptive effect under immune system interaction. In addition, the participation of the NO/cGMP/KATP pathway in the peripheral antinociception has been established by our group as the molecular mechanism of another adrenoceptor agonist xylazine. Thus the aim of this study was to obtain pharmacological evidences for the involvement of the NO/cGMP/KATP pathway in the peripheral antinociceptive effect induced by exogenous noradrenaline. The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E2 (2μg/paw). All drugs were locally administered into the right hind paw of male Wistar rats. NA (5, 20 and 80ng/paw) elicited a local inhibition of hyperalgesia. The non-selective NO synthase inhibitor l-NOarg (12, 18 and 24μg/paw) antagonized the antinociception effect induced by the highest dose of NA. The soluble guanylyl cyclase inhibitor ODQ (25, 50 and 100μg/paw) antagonized the NA-induced effect; and cGMP-phosphodiesterase inhibitor zaprinast (50μg/paw) potentiated the antinociceptive effect of NA low dose (5ng/paw). In addition, the local effect of NA was antagonized by a selective blocker of an ATP-sensitive K+ channel, glibenclamide (20, 40 and 80μg/paw). On the other hand, the specifically voltage-dependent K+ channel blocker, tetraethylammonium (30μg/paw), Ca2+-activated K+ channel blockers of small and large conductance types dequalinium (50μg/paw) and paxilline (20μg/paw), respectively, were not able to block local antinociceptive effect of NA. The results provide evidences that NA probably induces peripheral antinociceptive effects by activation of the NO/cGMP/KATP pathway.