Peripheral analgesic blockade of hypernociception: Activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K ⁺ channel pathway

Abstract

The final step in the direct restoration of the nociceptor threshold by peripheral administration of morphine and dipyrone was recently suggested to result from the opening of ATP-sensitive K ؉ channels (K ATP ؉ ). This channel is known to be open either directly by cGMP or indirectly via protein kinase G (PKG) stimulation. In the present study, it was shown that the blockade was caused by a specific PKG inhibitor (KT5823) of the antinociceptive effect of morphine and dipyrone on acute hypernociception and of dipyrone on persistent hypernociception. It was also shown that, in both models, KT5823 prevented the peripheral antinociceptive effect of an analogue of cGMP, the nitric oxide (NO) donor (S-nitroso-Nacetyl-D,L-penicilamine). However, in acute hypernociception, KT5823 did not prevent the peripheral antinociceptive effect of diazoxide (a direct K ATP ؉ opener). In persistent hypernociception, the sensitization plateau was induced by daily injections of prostaglandin E 2 (PGE2, 100 ng) into the rat paw for 14 days. After cessation of PGE 2 injections, the pharmacological blockade of persistent hypernociception led to a quiescent phase in which a rather small stimulus restored the hypernociceptive plateau. T he suggestion that the main mechanism of action of aspirin and aspirin-like drugs is due to the prevention of nociceptor sensitization (development of hyperalgesia) is now broadly accepted (1). In contrast with specific cyclooxygenase (COX)-1 and -2 inhibitors, some analgesics, such as morphine, dipyrone, diclofenac, and keterolac are able to directly block ongoing nociceptor sensitization, as shown by its blockade of acute prostaglandin E 2 -(PGE 2 ) induced hypernociception in rat hind paws (2-5). In 1979, the peripheral antinociceptive effect of opioids was discovered; this discovery led to the understanding that hypernociception (induced by inflammation or directly by inflammatory mediators) was essential for the manifestation of peripheral hypernociception (2, 6). In these studies, it was shown that the analgesic action of encephalin derivatives that did not cross the blood-brain barrier (e.g., BW180c and Tyr-D-Ala-GlyPhe) was achieved when the drugs were given systemically. At that time and based on these observations, the possibility of developing strong peripheral analgesics was suggested, a suggestion recently rediscovered by Stein et al. (7). These pioneering observations were confirmed over the next decade by Ferreira and coworkers (8-10) and by other scientists, notably Smith and coworkers (11-16). More recently, other groups have become interested in this area (17)(18)(19).Our serendipitous discovery of the opiates' peripheral antinociceptive activity was a corollary of the observation that morphine inhibited the activation of adenylyl cyclase (20), because we had proposed that inflammatory hyperalgesia was due to stimulation of the neuronal adenosine cAMP͞Ca 2ϩ pathway (21). In this work, following the idea that in several biological systems guanosine cGMP has the opposite effect of cAMP (22)...

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

“…In the case of the latter, this pathway might cause a hyperpolarization of nociceptive neurons, counteracting their enhanced excitability during the inflammatory process. In the schematic representation of the present hypothesis, we also indicate the possible mechanism of NO modulating K ATP currents indirectly through the activation of cGMP/PKG signaling (33). The development of drugs that mimic the action of morphine on this pathway may represent strategies for the treatment of inflammatory pain.…”

The antinociceptive effects of magnesium sulfate and MK-801 in visceral inflammatory pain model: The role of NO/cGMP/K+ATP pathway

“…These contradictions might be explained by considering that NO is a controversial molecule with dual effects, depending on its concentrations, NOS isoforms, redox balance, and the function of neuron subpopulations (Kawabata, 1994;Zhang et al, 2006). On one hand, increased NO production has been shown to produce antinociception (Bulutcu et al, 2002;Galdino et al, 2010;Garrido-Suárez et al, 2009;Granados-Soto et al, 1997;Sachs et al, 2004), on the other hand, NOS inhibitors elicit antinociception in some models of acute and persistent pain (De Alba et al, 2006;Milovanović et al, 2009;Yonehara et al, 1997).…”

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

“…Interestingly, other potassium channels blockers such as tetraethylammonium or 4-aminopyridine had no effect on the antinociception. Several of these reports indicate a linkage between the cyclic GMP signalling pathway and activation of K ATP (Lazaro-Ibanez et al 2001;Soares and Duarte 2001;Sachs et al, 2004). Indeed, studies of other cellular systems have demonstrated that cyclic GMP can lead to the activation of K ATP (Kubo et al 1994;Murphy and Brayden, 1995;Armstead 1997Armstead , 1998Schwingshackl et al 2002).…”