Additive antinociceptive effect of the combination of diazoxide, an activator of ATP-sensitive K+ channels, and sodium nitroprusside and dibutyryl-cGMP.
Using the rat paw pressure test, in which increased sensitivity is induced by intraplantar injection of prostaglandin E2, we assessed the antinociceptive effect of the ATP-sensitive K+ channel opener diazoxide and the large-conductance Ca(2+)-activated K+ channel opener NS-1619 (1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl) phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one) on the peripheral hyperalgesia induced by prostaglandin E2. Diazoxide, administered locally into the right hindpaw (20, 38, 75, 150, 300 and 600 microg), elicited a dose-dependent antinociceptive effect on prostaglandin E2-induced hyperalgesia (2 microg/paw). The effect of diazoxide at the dose of 300 microg/paw was shown to be local since it did not produce any effect when administered in the contralateral paw. The action of diazoxide (300 microg/paw) as an ATP-sensitive K+ channel opener seems to be specific, since its effect was antagonized in a dose-dependent manner by glibenclamide (40, 80 and 160 microg/paw), a specific blocker of these channels, while tetraethylammonium (7.5, 15 and 30 microg/paw), dequalinium (12.5, 25 and 50 microg/paw) or charybdotoxin (0.5, 1 and 2 microg/paw), blockers of voltage-dependent K+ channels and of small- and large-conductance Ca(2+)-activated K+ channels, respectively, were not able to abolish the antinociception induced by diazoxide. The peripheral antinociceptive effect of diazoxide was not prevented by prior administration of naloxone (12.5, 25 and 50 microg/paw), an opioid receptor antagonist, or methylene blue (75, 125 and 300 microg/paw), an agent that inhibits the activation of guanylate cyclase by nitric oxide. A low dose of diazoxide (20 microg/paw) administered together with a low dose of sodium nitroprusside (125 microg/paw) or dibutyryl cGMP (db-cGMP, 50 microg/paw) induced a marked antinociceptive effect similar to that observed when each drug was administered alone. NS1619 (75, 150 and 300 microg/paw), a specific opener of large-conductance Ca(2+)-activated K+ channels, had no antinociceptive action on prostaglandin E2-induced hyperalgesia. This series of experiments provides evidence for a peripheral antinociceptive action of diazoxide and supports the suggestion that the activation of ATP-sensitive K+ channels could be the mechanism by which sodium nitroprusside and db-cGMP induce peripheral antinociception, excluding the involvement of large-contuctance Ca(2+)-activated K+ channels in the process.
Alves
Daniela P
DP
Department of Pharmacology, Institute of Biological Sciences, UFMG, Av. Antônio Carlos, 6622-Campus da Pampulha, CEP 31.270.100, Belo Horizonte MG, Brazil.
Soares
Adriana C
AC
Francischi
Janetti N
JN
Castro
Maria S A
MS
Perez
Andréa C
AC
Duarte
Igor D G
ID
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology*; D003995:Dibutyryl Cyclic GMP / Q000494:pharmacology*; D015232:Dinoprostone; D004357:Drug Synergism; D004723:Endorphins / Q000502:physiology; D006930:Hyperalgesia / Q000139:chemically induced / Q000523:psychology; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins / Q000819:agonists / Q000187:drug effects*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels; D051381:Rats; D017208:Rats, Wistar
D000700:Analgesics; D001562:Benzimidazoles; D004723:Endorphins; D008565:Membrane Proteins; D009292:Narcotic Antagonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; C086491:NS 1619; D009599:Nitroprusside; D009569:Nitric Oxide; D003995:Dibutyryl Cyclic GMP; D009270:Naloxone; D015232:Dinoprostone; D003981:Diazoxide