Lan Ji Huang, et al. transmitter, modulated by inhibitory GABA-releasing interneurons.29,30 GABA is thought to be released from the interneurons upon feed-forward inhibition by granule cells or feedback inhibition by pyramidal cells.31 On the other hand, cGMP appears to be involved in GABA release, having effects of its own as well as a part of the nitric oxide- cGMP pathway. It would therefore, appear that cGMP analog increases the synaptic GABA release to labeled paraventricular nucleus neurons.32,33 And increasing cGMP level by superfusing slices with another phosphodiesterase inhibitor (zaprinast) increases GABA release in the brain stem, while a guanylyl cyclase inhibitor (ODQ) reduces GABA release.15 Recently, it has been demonstrated that potassium channels are downstream effectors of cGMP on GABA release.33 Furthermore, the antinociception provoked by sildenafil and dibutyryl-cGMP was reversed by potas- sium channel blockers.10,34 These findings together suggest that intravenous sildenafil increases the cGMP level by inhibition of phosphodiesterase 5 and then induces the release of GABA through a downstream mechanism, involving potassium channels which act on GABA recep- tors, in turn leading to an antinociceptive effect. As mentioned earlier, the activity of phosphodiesterase 5 was demonstrated in arterial and venous smooth muscle cells.17 Moreover, phosphodiesterase 5 activity seemed to be relevant to cGMP-linked vasodilatation.19 It is, therefore, possible that phosphodiesterase 5 inhibitor may have signi- ficant effect on hemodynamics. In this study, intravenous sildenafil at the highest dosage used decreased MAP. On the other hand, no significant change of HR response was noted after intravenous sildenafil administration. Previous studies showed modest effect of sildenafil on hemodyna- mics. Oral sildenafil moderately reduced blood pressure in normal humans.35 Furthermore, a significant decrease of blood pressure was transiently observed with intravenous sildenafil in healthy men, whereas HR was not affected.36 Particularly, the combination of sildenafil with nitric oxide donors can potentiate the hypotensive effect by accumula- tion of cGMP.37 Therefore, the concomitant use of sildenafil with any drug which serves as a nitric oxide donor is absol- utely contraindicated in clinics.38 Taken together, the current study provided an important information about the signaling mechanisms through which cGMP modulates the GABA receptors. These experiments indicate that intravenous sildenafil attenuated mechanical allodynia evoked by the ligation of spinal nerve. Such antinociception may be mediated through GABAA and GABAB receptors. This new information is expected to deepen our understanding of the role of GABA receptors for the action of intravenous sildenafil and indicates a usefulness of sildenafil for neuropathic pain as a treatment strategy. Furthermore, hemodynamic effect of intravenous sildenafil should carefully be evaluated when given with other antihypertensive drugs. ACKNOWLEDGEMENTS This work was supported Pfizer Pharmaceuticals Korea Ltd. (Grant number: IG-KOR-020-2005). REFERENCES 1. Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007;132:237-51. 2. Finnerup NB, Sindrup SH, Jensen TS. Chronic neuropathic pain: mechanisms, drug targets and measurement. Fundam Clin Pharmacol 2007;21:129-36. 3. Wallace JM. Update on pharmacotherapy guidelines for treat- ment of neuropathic pain. Curr Pain Headache Rep 2007;11:208- 14. 4. Chizh BA, Göhring M, Tröster A, Quartey GK, Schmelz M, Koppert W. 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Kim WM, Yoon MH, Lee HG, Han YG, Kim YO, Huang LJ, et 86 Yonsei Med J http://www.eymj.org Volume 51 Number 1 January 2010