The Antiallodynic Effects of Intrathecal Zaprinast in Rats with Chronic Constriction Injury of the Sciatic Nerve

BACKGROUND: Zaprinast is an inhibitor of phosphodiesterase 5, 6 and 9. Phosphodiesterase inhibitors could produce anti-nociceptive effects by promoting the accumulation of cGMP. We hypothesized that intrathecal zaprinast could attenuate the allodynia induced by chronic constriction injury of the sciatic nerve in rat. METHODS: Sprague-Dawley rats were prepared with four loose ligations of the left sciatic nerve just proximal to the trifurcation into the sural, peroneal and tibial nerve branches. Tactile allodynia was measured by applying von Frey filaments to the lesioned hindpaw. The thresholds for the withdrawal responses were assessed. Zaprinast (3-100microg) was administered intrathecally by the direct lumbar puncture method to obtain the dose-response curve and the 50% effective dose (ED50). Measurements were taken before and 15, 30, 45, 60, 90, 120, and 180 min after the intrathecal doses of zaprinast. The side effects were also observed. RESULTS: Intrathecal zaprinast resulted in a dose-dependent antiallodynic effect. The maximal effects occurred within 15-30 min and then they gradually decreased down to the baseline level over time in all the groups. There was a dose dependent increase in the magnitude and duration of the effect. The ED50 value was 17.4microg (95% confidence intervals; 14.7-20.5microg). No severe motor weakness or sedation was observed in any of the rats. CONCLUSIONS: Intrathecally administered zaprinast produced a dose-dependent antiallodynic effect in the chronic constriction injury neuropathic pain model. These findings suggest that spinal phosphodiesterase 5, 6 and 9 may play an important role in the modulation of neuropathic pain.

The Role of Adrenergic and Cholinergic Receptors on the Antinociception of Intrathecal Zaprinast in the Formalin Test of Rats / 대한마취과학회지

BACKGROUND: Spinal zaprinast, phospodiesterase inhibitor, has been shown to have an antinociception through an increase of cGMP. The aim of this study was to examine the role of spinal adrenergic and cholinergic receptors on the antinociceptive action of intrathecal zaprinast. METHODS: Rats were implanted with lumbar intrathecal catheters. After formalin injection, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. After observing the effect of intrathecal zaprinast, antagonism of intrathecal prazosin, yohimbine, atropine and mecamylamine for the effect of zaprinast were evaluated. RESULTS: Intrathecal zaprinast produced a dose-dependent suppression of formalin-induced flinches in both phases of the formalin test. Intrathecal prazosin reversed the antinociception of zaprinast in phase 2, but not phase 1. Intrathecal yohimbine reversed the antinociception of zaprinast in both phases. Neither atropine nor mecamylamine reversed the antinocicetive action of zaprinast. CONCLUSIONS: Intrathecal zaprinast is against the nociceptive state evoked by formalin stimulus. Alpha 2 or alpha 1 adrenergic receptor, but not cholinergic receptors, may be related to the action of zaprinast in the spinal cord.

Effect of Zaprinast, a Phosphodiesterse Inhibitor, on Formalin-induced Nociception and Hemodynamics in the Rat Spinal Cord / 대한마취과학회지

BACKGROUND: Cyclic guanosine monophosphate (cGMP) is involved in antinociception and vascular relaxation. The effects of zaprinast, which increases the level of cGMP by inhibiting phosphodiesterase, in the spinal cord have not been reported. The aims of this study were to evaluate the effects of intrathecal zaprinast on stimulus evoked by formalin injection, and to observe hemodynamic change in the absence of formalin stimulation. METHODS: Rats were implanted with lumbar intrathecal catheters. Intrathecal zaprinast was administered 10 min before formalin injection. After formalin injection, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. Mean arterial pressure (MAP) and heart rate (HR) were measured after intrathecal delivery of zaprinast for a period of 60 min. RESULTS: Intrathecal administration of zaprinast produced a dose-dependent suppression of flinches in both phases. Zaprinast had no evident effects on baseline MAP or HR. CONCLUSIONS: Zaprinast, a phosphodiesterase inhibitor, is active against the nociceptive state evoked by formalin stimulus without affecting resting MAP or HR. Accordingly, spinal zaprinast may be useful in the management of tissue-injury induced pain.

Antinociceptive Effect of the Intrathecal Phosphodiesterase Inhibitor, Zaprinast, in a Rat Formalin Test / 대한통증학회지

BACKGROUND: Cyclic guanosine monophosphate (cGMP) and opioid receptors are involved in the modulation of nociception. Although the opioid receptors agonists are active in pain, the effect of an phospodiesterase inhibitor (zaprinast) for increasing the level of cGMP has not been thoroughly investigated at the spinal level. This study examined the effects of intrathecal zaprinast and morphine in a nociceptive test and we also examined the nature of the pharmacological interaction after the coadministration of zaprinast with morphine. The role of the nitric oxide(NO)-cGMP-potassium channel pathway on the effect of zaprinast was further clarified. METHODS: Catheters were inserted into the intrathecal space of male SD rats. For the induction of pain, 50microliter of 5% formalin solution was applied to the hindpaw. Isobolographic analysis was used for the evaluation of the drug interaction between zaprinast and morphine. Furthermore, NO synthase inhibitor (L-NMMA), guanylyl cyclase inhibitor (ODQ) or a potassium channel blocker (glibenclamide) were intrathecally administered to verify the involvement of the NO-cGMP-potassium channel pathway on the antinociception effect of zaprinast. RESULTS: Both zaprinast and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after the intrathecal administration of the zaprinast-morphine mixture in both phases. Intrathecal L-NMMA, ODQ and glibenclamide did not reverse the antinociception of zaprinast in either phase. CONCLUSIONS: These results suggest that zaprinast, morphine and the mixture of the two drugs are effective against acute pain and they facilitated pain state at the spinal level. Thus, the spinal combination of zaprinast with morphine may be useful for the management of pain. However, the NO-sensitive cGMP-potassium channel pathway did not contribute to the antinocieptive mechanism of zaprinast in the spinal cord.