The dual effect of a nitric oxide donor in nociception

Sousa, Ângela Maria; Prado, Wiliam A.

doi:10.1016/s0006-8993(01)01995-3

Cited by 171 publications

(114 citation statements)

References 65 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…In addition, intrathecal 8-Br-cGMP suppressed the flinching behavior produced by the injection of formalin into the hind paw (Tegeda et al 2002). Interestingly, these antinociceptive effects were produced by low dosages of these agents, however, higher dosages of SIN-1 or 8-Br-cyclic GMP had pronociceptive effects in these animal models (Sousa et al 2001;Tegeda et al 2002). Furthermore, the exact nature of the analgesic properties of cyclic GMP in the periphery are now unclear.…”

Section: Discussionmentioning

confidence: 98%

“…This exact role of cyclic GMP is complicated further by recent findings. Intrathecal delivery of SIN-1, a nitric oxide donor, was capable of reducing the mechanical hyperalgesia resulting from injury to the sciatic nerve (Sousa et al 2001). In addition, intrathecal 8-Br-cGMP suppressed the flinching behavior produced by the injection of formalin into the hind paw (Tegeda et al 2002).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

2007

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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

2007

View full text Add to dashboard Cite

show abstract

“…In fact, depending on the nociceptive system level (central or periphery) and the amount of NO, it could have either antinociceptive or pronociceptive actions. For instance, in the spinal cord, low and high concentrations of NO cause antinociception and nociception, respectively (11). Furthermore, even in the periphery, the stimulation of the NOS/NO pathway in the epidermis and dermis causes mechanical hyper-and antinociception, respectively (12,13).…”

Section: Cfa-induced Hypernociceptionmentioning

confidence: 99%

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.

180

187

View full text Add to dashboard Cite

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...

show abstract

“…In recent years, classical von Frey filaments have become popular among mechanical tests applied to rats (3)(4)(5), although this test presents some disadvantages such as the large number of attempts required to evaluate the nociceptive threshold and the problems with the standardization of the filaments (6). The electronic pressure-meter has been previously used in humans (7) and rats (8).…”

Section: Introductionmentioning

confidence: 99%

An electronic pressure-meter nociception paw test for rats

Vivancos

Verri

Cunha

et al. 2004

Braz J Med Biol Res

194

116

View full text Add to dashboard Cite

The objective of the present investigation was to compare the sensitivity of an electronic nociceptive mechanical paw test with classical mechanical tests to quantify the intensity variation of inflammatory nociception. The electronic pressure-meter test consists of inducing the hindpaw flexion reflex by poking the plantar region with a polypropylene pipette tip adapted to a hand-held force transducer. This method was compared with the classical von Frey filaments test and with the rat paw constant pressure test, a modification of the Randall and Selitto test developed by our group. When comparing the three methods, the electronic pressure-meter and the rat paw constant pressure test, but not the von Frey filaments test, detected time vs treatment interactions in prostaglandin E 2 (PGE 2 )-induced hypernociception. Both methods also detected the PGE 2 -induced hypernociception in dose-(50-400 ng/ paw) and time-(1-4 h) dependent manners, and time vs treatment interactions induced by carrageenin (25-400 µg/paw). Furthermore, the electronic pressure-meter test was more sensitive at early times, whereas the constant pressure test was more sensitive at later times. Moreover, the electronic pressure-meter test detected the dose-dependent antinociceptive effect of local indomethacin (30-300 µg/paw) and dipyrone (80-320 µg/paw) on carrageenin-(200 µg/paw) and PGE 2 -(100 ng/paw) induced hypernociception, respectively, and also detected the ineffectiveness of indomethacin (300 µg) on the effect of PGE 2 . Our results show that the electronic pressure-meter provides a sensitive, objective and quantitative mechanical nociceptive test that could be useful to characterize new nociceptive inflammatory mediators and also to evaluate new peripheral analgesic substances. Correspondence

show abstract

The dual effect of a nitric oxide donor in nociception

Cited by 171 publications

References 65 publications

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

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

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

An electronic pressure-meter nociception paw test for rats

Contact Info

Product

Resources

About

The dual effect of a nitric oxide donor in nociception

Cited by 171 publications

References 65 publications

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

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

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

An electronic pressure-meter nociception paw test for rats

Contact Info

Product

Resources

About

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