Sildenafil and Neuropathic Pain/Hemodynamics The extent of change of MAP was not statistically signi- ficant compared to baseline value over the 60 min-period Fig. 2. The effects of intravenous bicuculline (16 mg/kg, n = 7) and saclofen (16 mg/kg, n = 8) on the antinociception by intravenous sildenafil (30 mg/kg) in spinal nerve ligation-induced neuropathic pain. Bicuculline and saclofen were administered 10 min before the delivery of sildenafil. Data are presented as %MPE. Both bicuculline and saclofen attenuated the antinociception of sildenafil. Neither bicuculline (n = 5) nor saclofen (n = 6) alone affected the control response. Each bar represents mean ± SEM. Compared with sildenafil, *p < 0.05, p < 0.01. A B Fig. 3. Temporal effect of intravenous saline and sildenafil (n = 25) on mean arterial pressure (MAP, A) and heart rate (HR, B). Saline (control) and sildenafil were administered at time 0. Percent change of MAP and HR from baseline is plotted against time. Each line represents mean ± SEM. Compared with baseline, *p < 0.05. following the administration of intravenous sildenafil (1, 3, 10 mg/kg). However, 30 mg/kg of sildenafil significantly augmented the extent of decrease of MAP at 5, 10 and 20 min (p < 0.05) (Fig. 3A). The extent of change of HR was not statistically significant compared with baseline value following intravenous sildenafil administration (Fig. 3B). DISCUSSION Neuropathic pain occurs as a result of various conditions that cause functional abnormalities or direct injury in the nervous system or many diseases such as diabetic neuro- pathy, postherpetic neuralgia, and trigeminal neuralgia.1-3 Central sensitization is the main contributor to the develop- ment of neuropathic pain. The related symptoms are the aberrant responses encountered in animal models and by patients (i.e., hyperalgesia and allodynia).4,5 It is estimated to afflict millions of people worldwide with neuropathic pain. A previous study reported that a population prevalence of neuropathic pain was about 8%.24 The management of neuropathic patients is complex, and responses of patients to treatments are inconsistently noted.25,26 Even with well- established neuropathic medications, effectiveness is ina- dequate and undesirable side effects are also troublesome.25,26 Thus, those phenomena have led to the development of treatment modality that can be used in clinical practice. In the present study, intravenous sildenafil was found to increase the paw withdrawal threshold after spinal nerve ligation. Therefore, it is conceivable that the increased cGMP level by inhibition of phosphodiesterase 5 may contribute to the attenuation of the neuropathic pain at a systemic level. Phosphodiesterase enzymes occur widely in biological systems and are present in mammalian tissues.27 Phospho- diesterase is an enzyme involved in the hydrolysis of cGMP, and 11 subtypes of phosphodiesterase isoenzymes have been identified on the basis of their functional characteris- tics, such as substrate specificity, cellular distribution and susceptibility to selective inhibitors.28 Among these isoen- zymes, type 5 phosphodiesterase exerts the most signifi- cant effect on the hydrolysis of cGMP.7 Of particular interest, cGMP may play a pivotal role in the antinocicep- tive mechanism. Several studies have indicated that dibutyryl-cGMP, 8-bromo-cGMP and sildenafil produce antinociception in various types of noxious stimulation.7,10-14 On the other hand, intravenous GABAA antagonist (bicu- culline) and GABAB antagonist (saclofen) blocked the antinociceptive effect of intravenous sildenafil in the present study. These findings suggest that both GABAA and GABAB receptors may contribute to the action of sildenafil at a systemic level. In the hippocampus, GABA is the main inhibitory neuro- Yonsei Med J http://www.eymj.org Volume 51 Number 1 January 2010 85