Activation of ATP-sensitive K+ channels: mechanism of peripheral antinociceptive action of the nitric oxide donor, sodium nitroprusside

Soares, Adriana C.; Leite, Rômulo; Tatsuo, M.A.K.F.; Duarte, Igor Dimitri Gama

doi:10.1016/s0014-2999(00)00355-1

Cited by 120 publications

(65 citation statements)

References 25 publications

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“…5E). These results corroborate the following findings: (i) the up-regulation of K ATP by NO was recently shown in primary sensitive neurons (24); (ii) in vivo NO donor-reduced, PGE 2 -induced hypernociception was prevented by treatment with glibenclamide (25); and (iii) intratecal treatment of rats with ODN antisenses against Kir6.2 and SUR1, two different subunits of K ATP that are expressed by DRG neurons (26), prevented morphine and NO-donor antinociceptive effects (Fig. S7 A and B).…”

Section: Cfa-induced Hypernociceptionsupporting

confidence: 92%

Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/K _ATP signaling pathway

Cunha

Roman‐Campos

Lotufo

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

188

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Morphine is one of the most prescribed and effective drugs used for the treatment of acute and chronic pain conditions. In addition to its central effects, morphine can also produce peripheral analgesia. However, the mechanisms underlying this peripheral action of morphine have not yet been fully elucidated. Here, we show that the peripheral antinociceptive effect of morphine is lost in neuronal nitric-oxide synthase null mice and that morphine induces the production of nitric oxide in primary nociceptive neurons. The activation of the nitric-oxide pathway by morphine was dependent on an initial stimulation of PI3Kγ/AKT protein kinase B (AKT) and culminated in increased activation of K ATP channels. In the latter, this intracellular signaling pathway might cause a hyperpolarization of nociceptive neurons, and it is fundamental for the direct blockade of inflammatory pain by morphine. This understanding offers new targets for analgesic drug development.M orphine is one of the most prescribed and effective drugs used for treatment of postoperatory and acute severe pain. Nevertheless, its use is frequently limited by undesirable side effects including respiratory depression, tolerance, and addiction. The discovery that morphine can also produce peripheral analgesia in the setting of inflammatory pain opened the possibility of developing peripheral restricted opioids devoid of central side effects (1).Morphine peripheral analgesia was discovered by its direct effect on already established inflammatory hypernociception induced by prostaglandin E 2 (PGE 2 ) injected in rat hind paws (1). Therefore, in contrast to aspirin-like drugs whose analgesic mechanism depends on prevention of nociceptor sensitization by inhibiting synthesis of prostaglandins, opioids are able to directly block ongoing nociceptor sensitization. However, the molecular mechanisms triggered by morphine to promote this action have not been fully elucidated. The present study reports on a series of experiments using behavioral, biochemical, and electrophysiological approaches to address this issue. The following major findings are reported herein: (i) the activation of peripheral opioid receptors in primary nociceptive neurons by morphine triggers a cascade of intracellular signaling events initiated by PI3Kγ/Protein kinase B (AKT); (ii) this is accompanied by activation of neuronal nitric oxide synthase (nNOS) and nitric oxide (NO) production, which (iii) induces an increase in K ATP channel currents; and (iv) it causes a hyperpolarization of nociceptive neurons. Results and DiscussionBased on the evidence that cAMP was the key intracellular second messenger involved in PGE 2 -induced nociceptor sensitization (2) and that opioid-receptor activation in vitro was coupled to adenylyl-cyclase inhibition (3), it was initially suggested that these drugs counteracted inflammatory hypernociception directly through inhibition of PGE 2 -induced adenylyl-cyclase activation (1, 4). Subsequent in vitro studies, which confirmed the ability of opioids to inhibit ad...

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Section: Cfa-induced Hypernociceptionsupporting

confidence: 92%

Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/K _ATP signaling pathway

Cunha

Roman‐Campos

Lotufo

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

188

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“…Morphine has been shown to exert its peripheral antinociceptive effect by activating ATP-sensitive K + channels (17). Recent studies carried out in our laboratory demonstrated that the peripheral antinociceptive action of the nitric oxide donor sodium nitroprusside (26) and dibutyryl cGMP (27) is associated with ATP-sensitive K + channels, thus establishing a link between the participation of the nitric oxide/cGMP pathway in the analgesia induced by certain drugs and the activation of ATP-sensitive K + channels.…”

Section: Discussionmentioning

confidence: 87%

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

Rodrigues

Castro

Francischi

et al. 2005

Braz J Med Biol Res

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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.

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“…Behavioral studies of nociceptive sensitivity indicate a link between activation of the nitric oxide/cyclic GMP pathway and the antinociceptive actions of K ATP (see Soares et al 2000;Lazaro-Ibanez et al 2001;Soares and Duarte 2001). Based on these findings, we explored the idea that 8-Br-cyclic GMP, like diazoxide, might reduce the sensitization caused by PGE 2 and that glibenclamide, an inhibitor of K ATP current, could reverse this 8-Br-cyclic GMP-induced suppression.…”

Section: Effects Of 8-br-cyclic Gmp and Glibenclamide On The Sensitizmentioning

confidence: 99%

ATP-sensitive potassium currents reduce the PGE2-mediated enhancement of excitability in adult rat sensory neurons

2007

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Behavioral studies have shown that the hyperalgesia arising from inflammatory agents, such as prostaglandin E 2 (PGE 2 ) can be antagonized by activators of the ATP-sensitive potassium current (K ATP ). This observation raises questions as to whether this suppression results from a direct action on sensory neurons and what are the cellular mechanisms giving rise to this inhibition. We found that small to medium diameter sensory neurons isolated from the L4-6 DRGs expressed the mRNAs for Kir6.1, Kir6.2, and SUR1. In perforated-patch clamp recordings from acutely dissociated sensory neurons from the young adult rat, exposure to 300 μM diazoxide, a K ATP channel agonist, significantly hyperpolarized the resting membrane potential, reduced the number of action potentials evoked by a ramp of depolarizing current, and increased the amplitude of inward K ATP currents evoked by the voltage ramp. Similar results were obtained with the protonophore FCCP, which is known to reduce the levels of intracellular ATP and lead to the activation of K ATP . Only a subpopulation of sensory neurons was sensitive to diazoxide whereas other neurons were unaffected. Treatment with 1 μM PGE 2 significantly enhanced the excitability of these small to medium diameter capsaicin-sensitive sensory neurons; this enhancement was reversed by subsequent exposure to diazoxide in a subpopulation of neurons. Similar to diazoxide, exposure to 8-Br-cyclic GMP antagonized the PGE 2 -induced increase in excitability. The effects of 8-Br-cyclic GMP could be reversed by exposure to glibenclamide, an antagonist of K ATP channels. As with diazoxide, only a subpopulation of sensory neurons were affected by 8-Br-cyclic GMP. These results demonstrate that activation of K ATP can reverse the sensitization produced by PGE 2 and may be an important means to modulate the enhanced excitability that results from inflammatory or injury conditions.

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Activation of ATP-sensitive K+ channels: mechanism of peripheral antinociceptive action of the nitric oxide donor, sodium nitroprusside

Cited by 120 publications

References 25 publications

Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/K _ATP signaling pathway

Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/K _ATP signaling pathway

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

ATP-sensitive potassium currents reduce the PGE2-mediated enhancement of excitability in adult rat sensory neurons

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Activation of ATP-sensitive K+ channels: mechanism of peripheral antinociceptive action of the nitric oxide donor, sodium nitroprusside

Cited by 120 publications

References 25 publications

Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/K ATP signaling pathway

Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/K ATP signaling pathway

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

ATP-sensitive potassium currents reduce the PGE2-mediated enhancement of excitability in adult rat sensory neurons

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Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/K _ATP signaling pathway

Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/K _ATP signaling pathway