Participation of ATP-sensitive K+ channels in the peripheral antinociceptive effect of fentanyl in rats

Abstract

We examined the effect of several K + channel blockers such as glibenclamide, tolbutamide, charybdotoxin (ChTX), apamin, tetraethylammonium chloride (TEA), 4-aminopyridine (4-AP), and cesium on the ability of fentanyl, a clinically used selective µ-opioid receptor agonist, to promote peripheral antinociception. Antinociception was measured by the paw pressure test in male Wistar rats weighing 180-250 g (N = 5 animals per group). Carrageenan (250 µg/ paw) decreased the threshold of responsiveness to noxious pressure (∆ = 188.1 ± 5.3 g). This mechanical hyperalgesia was reduced by fentanyl (0.5, 1.5 and 3 µg/paw) in a peripherally mediated and dosedependent fashion (17.3, 45.3 and 62.6%, respectively). The selective blockers of ATP-sensitive K + channels glibenclamide (40, 80 and 160 µg/paw) and tolbutamide (80, 160 and 240 µg/paw) dose dependently antagonized the antinociception induced by fentanyl (1.5 µg/paw). In contrast, the effect of fentanyl was unaffected by the large conductance Ca 2+ -activated K + channel blocker ChTX (2 µg/paw), the small conductance Ca 2+ -activated K + channel blocker apamin (10 µg/paw), or the non-specific K + channel blocker TEA (150 µg/paw), 4-AP (50 µg/paw), and cesium (250 µg/paw). These results extend previously reported data on the peripheral analgesic effect of morphine and fentanyl, suggesting for the first time that the peripheral µ-opioid receptor-mediated antinociceptive effect of fentanyl depends on activation of ATP-sensitive, but not other, K + channels.

Loss of SUR1 subtype KATP channels alters antinociception and locomotor activity after opioid administration

“…Mechanically evoked thresholds were significantly attenuated in the SUR1-deficient mice for all opioids tested. This is in line with previous studies which found fentanyl analgesia could be attenuated by intraplantar administration of KATP channel antagonists (Rodrigues et al, 2005) and icv administration of the KATP channel agonist cromakalim could enhance antinociception produced by buprenorphine and morphine (Ocaña et al, 1995). Hyperlocomotion was potentiated in SUR1 KO mice after morphine and buprenorphine administration, but not after systemic delivery fentanyl or DAMGO.…”

Potassium Channels and Their Potential Roles in Substance Use Disorders

“…Blockers of ATP-sensitive class of K IR subfamily, glibenclamide and tolbutamide sulfonylureas, effectively reversed the peripheral antinociceptive effect of fentanyl [130]. Glibenclamide was also shown to play an active role in morphine reward [131] by facilitating morphine-induced conditioned place preference [132].…”

Antinociceptive effects of an ethanolic extract of Desmodium adscendens: possible involvement of opioidergic, adrenergic, potassium channels and serotoninergic pathways

“…Glibenclamide is an ATP-sensitive K + channel blocker which blocked the analgesic activity of both DAE and morphine. The opening of ATP-sensitive K + channel has been reported to participate in opioid-mediated antinociception at the level of K + and not opioid receptor activation [40][41][42]. It is well established that glibenclamide specifically blocks ATP sensitive K + channels, with no effect on Ca 2+ or voltage-dependent K + -channels [43].…”