Effect of Sildenafil on Neuropathic Pain and Hemodynamics in Rats

PURPOSE: The inhibition of phosphodiesterase 5 produces an antinociception through the increase of cyclic guanosine monophosphate (cGMP), and increasing cGMP levels enhance the release of gamma-aminobutyric acid (GABA). Furthermore, this phosphodiesterase 5 plays a pivotal role in the regulation of the vasodilatation associated to cGMP. In this work, we examined the contribution of GABA receptors to the effect of sildenafil, a phosphodiesterase 5 inhibitor, in a neuropathic pain rat, and assessed the hemodynamic effect of sildenafil in normal rats. MATERIALS AND METHODS: Neuropathic pain was induced by ligation of L5/6 spinal nerves in Sprague-Dawley male rats. After observing the effect of intravenous sildenafil on neuropathic pain, GABAA receptor antagonist (bicuculline) and GABAB receptor antagonist (saclofen) were administered prior to delivery of sildenafil to determine the role of GABA receptors in the activity of sildenafil. For hemodynamic measurements, catheters were inserted into the tail artery. Mean arterial pressure (MAP) and heart rate (HR) were measured over 60 min following administration of sildenafil. RESULTS: Intravenous sildenafil dose-dependently increased the withdrawal threshold to the von Frey filament application in the ligated paw. Intravenous bicuculline and saclofen reversed the antinociception of sildenafil. Intravenous sildenafil increased the magnitude of MAP reduction at the maximal dosage, but it did not affect HR response. CONCLUSION: These results suggest that sildenafil is active in causing neuropathic pain. Both GABAA and GABAB receptors are involved in the antinociceptive effect of sildenafil. Additionally, intravenous sildenafil reduces MAP without affecting HR.

The Role of Adrenergic and Cholinergic Receptors on the Antinociception of Korean Red Ginseng in the Spinal Cord of Rats / 대한통증학회지

BACKGROUND: Experimental evidence indicates that ginseng modulate the nociceptive transmission. Authors examined the role of adrenergic and cholinergic receptors on the antinociceptive action of Korean red ginseng against the formalin-induced pain at the spinal level. METHODS: Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. Fifty microl of 5% formalin solution was injected to the hindpaw for induction of pain and formalin-induced pain (flinching response) was observed. The role of spinal adrenergic and cholinergic receptors on the effect of Korean red ginseng was assessed by antagonists (prazosin, yohimbine, atropine and mecamylamine). RESULTS: Intrathecal Korean red ginseng produced a dose-dependent suppression of the flinching response in the rat formalin test. All of prazosin, yohimbine, atropine and mecamylamine antagonized the antinociception of Korean red ginseng. CONCLUSIONS: Spinal Korean red ginseng is effective against acute pain and facilitated pain state evoked by formalin injection. All of alpha 1, alpha 2, muscarinic and nicotinic receptors may play an important role in the antinociceptive action of Korean red ginseng at the spinal level.

Effect of Intrathecal Ginsenosides on Mechanical Allodynia in a Neuropathic Rat Model

BACKGROUND: Traditionally, ginseng has been widely used to manage various types of diseases. In particular, the analgesic effect of ginsenosides has been reported for inflammatory pain. However, the effect of ginsenosides on neuropathic pain has not been determined. The aim of this study was to examine the effect of ginsenosides on neuropathic pain in the spinal cord. METHODS: Neuropathic pain was induced by ligation of the lumbar 5, 6 spinal nerves in male Sprague-Dawley rats. Intrathecal catheters were placed into the subarachnoid space of rats that presented with mechanical allodynia. Mechanical allodynia was evaluated by measuring the withdrawal threshold to a von Frey filament applied to the plantar surface of rats. The analgesic effect of intrathecal ginsenosides was observed at 15, 30, 60, 90, 120, 150 and 180 min after delivery of the ginsenosides. RESULTS: After nerve ligation, the paw withdrawal threshold was significantly decreased at the ligated site. At the doses used in this study, intrathecal ginsenosides did not alter the withdrawal threshold in the ligated paw during the entire observation period. However, a dose of intrathecal ginsenosides greater than 1,500microg caused motor impairment. CONCLUSIONS: These results suggest that ginsenosides may not have a direct modulatory role in the transmission of neuropathic pain at the spinal level.

Additive Antinociception between Intrathecal Sildenafil and Morphine in the Rat Formalin Test

The possible characteristics of spinal interaction between sildenafil (phosphodiesterase 5 inhibitor) and morphine on formalin-induced nociception in rats was examined. Then the role of the opioid receptor in the effect of sildenafil was further investigated. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. For induction of pain, 50 microliter of 5% formalin solution was applied to the hindpaw. Isobolographic analysis was used for the evaluation of drug interaction between sildenafil and morphine. Furthermore, naloxone was intrathecally given to verify the involvement of the opioid receptor in the antinociception of sildenafil. Both sildenafil and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. The isobolographic analysis revealed an additive interaction after intrathecal delivery of the sildenafil-morphine mixture in both phases. Intrathecal naloxone reversed the antinociception of sildenafil in both phases. These results suggest that sildenafil, morphine, and the mixture of the two drugs are effective against acute pain and facilitated pain state at the spinal level. Thus, the spinal combination of sildenafil with morphine may be useful in the management of the same state. Furthermore, the opioid receptor is contributable to the antinocieptive mechanism of sildenafil at the spinal level.

The Effect of Treatment with Intrathecal Ginsenosides in a Rat Model of Postoperative Pain / 대한통증학회지

BACKGROUND: Ginseng has been used to manage various types of pain in folk medicine. This study characterized the effect of treatment with intrathecal ginsenosides, the active components of ginseng in a postoperative pain model. METHODS: Male Sprague-Dawley rats were implanted with lumbar intrathecal catheters. An incision was made in the plantar surface of the hindpaw. Withdrawal thresholds following the application of a von Frey filament to the wound site were measured. To determine the role of the opioid or GABA receptors following treatment with the ginsenosides, naloxone, bicuculline (a GABAA receptor antagonist), and saclofen (a GABAB receptor antagonist) were administered intrathecally 10 min before the delivery of the ginsenosides and the changes of the withdrawal thresholds after application of the von Frey filament were observed. RESULTS: Treatment with the intrathecal ginsenosides increased the withdrawal threshold in a dose dependent manner. Pre-treatment with intrathecal naloxone reversed the antinociceptive effect of the ginsenosides. However, pre-treatment with intrathecal bicuculline and saclofen failed to have an effect on the activity of the ginsenosides. CONCLUSIONS: These results suggest that ginsenosides are effective to alleviate the postoperative pain evoked by paw incision. The opioid receptor, but not GABA receptors, may be involved in the antinociceptive action of the ginsenosides at the spinal level.

GABAB Receptor Modulation on the Antinociception of Intrathecal Sildenafil in the Rat Formalin Test / 대한통증학회지

BACKGROUND: A phosphodiesterase 5 inhibitor, sildenafil, has been effective against nociception. Several lines of evidence have demonstrated the role of the GABAergic pathway in the modulation of nociception. The impact of the GABA receptors on sildenafil was studied using the formalin test at the spinal level. METHODS: Male SD rats were prepared for intrathecal catheterization. The formalin test was induced by subcutaneous injection of formalin solution. The change in the activity of sildenafil was examined after pretreatment with GABA receptor antagonists (GABAA receptor antagonist, bicuculline; GABAB receptor antagonist, saclofen). RESULTS: Intrathecal sildenafil dose-dependently attenuated the flinching observed during phase 1 and 2 in the formalin test. The antinociceptive effect of sildenafil was reversed by the GABAB receptor antagonist (saclofen) but not by the GABAA receptor antagonist (bicuculline) in both phases. CONCLUSIONS: Intrathecal sildenafil suppressed acute pain and the facilitated pain state. The antinociception of sildenafil is mediated via the GABAB receptor, but not the GABAA receptor, at the spinal level.

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.

The Role of Opioid Receptor on the Analgesic Action of Intrathecal Sildenafil in Rats / 대한통증학회지

BACKGROUND: Intrathecal sildenafil has produced antinociception by increasing the cGMP through inhibition of phosphodiesterase 5. Spinal opioid receptor has been reported to be involved in the modulation of nociceptive transmission. The aim of this study was to examine the role of opioid receptor in the effect of sildenafil on the nociception evoked by formalin injection. METHODS: Rats were implanted with lumbar intrathecal catheters. Formalin testing was used as a nociceptive model. Formalin-induced nociceptive behavior (flinching response) was observed. To clarify the role of the opioid receptor for the analgesic action of sildenafil, naloxone was administered intrathecally 10 min before sildenafil delivery, and formalin was then injected 10 min later. RESULTS: Intrathecal sildenafil produced dose-dependent suppression of flinches in both phases during the formalin test. Intrathecal naloxone reversed the analgesic effect of sildenafil in both phases. CONCLUSIONS: Sildenafil is active against the nociceptive state that's evoked by a formalin stimulus, and the opioid receptor is involved in the analgesic action of sildenafil at thespinal level.