Role of PKG-L-type calcium channels in the antinociceptive effect of intrathecal sildenafil

Sildenafil increases the cyclic guanosine monophosphate (cGMP) by inhibition of a phosphodiesterase 5, thereby leading to an antinociceptive effect. The increased cGMP may exert the effect on an L-type calcium channel through the activation of protein kinase G (PKG). The purpose of this study was to examine the possible involvement of a PKG-L-type calcium channel on the effect of sildenafil at the spinal level. Catheters were inserted into the intrathecal space of male SD rats. Pain was induced by applying 50 microliter of a 5% formalin solution to the hindpaw. The sildenafil-induced effect was examined after an intrathecal pretreatment of a PKG inhibitor (KT 5823), or a L-type calcium channel activator (FPL 64176). Intrathecal sildenafil produced an antinociceptive effect during phase 1 (0~10 min interval) and phase 2 (10~60 min interval) in the formalin test. Intrathecal KT 5823 and FPL 64176 attenuated the antinociceptive effect of sildenafil during both phases. Sildenafil is effective against both acute pain and the facilitated pain state at the spinal level. In addition, the inhibition of an L-type calcium channel by activation of the PKG may contribute to the antinocieptive mechanism of sildenafil in the spinal cord.

Effect of ginsenosides in a mouse model of bone cancer pain

BACKGROUND: Ginsenosides have been used for a long time as an oriental folk medicine. Although ginsenosides modulate the nociceptive transmission, the effect of ginsenosides on a bone cancer pain has not been elucidated. The authors examined the effect of ginsenosides in a mouse model of bone cancer pain. METHODS: Bone cancer was induced by intramedullary injection of osteolytic sarcoma cells in to the femur in male C3H/HeJ mice. Mice showing mechanical allodynia after 14 days after cancer cells inoculation were included in this study. Mechanical allodynia was evaluated by measuring the withdrawal threshold to von Frey filament applying on the femoral cancer site. Effect of ginsenosides (30, 100, 300 mg/kg) was examined at 15, 30, 60, 90, 120 min after intraperitoneal administration of ginsenosides. RESULTS: After cancer cells injection into the femur, bone cancer was developed in simple X-ray. A paw withdrawal threshold in a cancer site was significantly decreased. Intraperitoneal ginsenosides did not effectively alter the withdrawal threshold in the cancer site. CONCLUSIONS: Taken together, ginsenosides may not be effective to attenuate the bone cancer pain.

The role of group III metabotropic receptors on opioid tolerance

BACKGROUND: Prolonged exposure to morphine causes tolerance to morphine-induced antinociception, yet the mechanisms of such tolerance are not fully understood. Although group I and II metabolic glutamate receptors (mGluRs) are involved in the modulation of morphine tolerance, the role of the group III mGluRs has not been determined. Therefore, we examined the effect of a group III mGluRs agonist on the morphine tolerance in the spinal cord. METHODS: An intrathecal infusion of morphine (40 nmol/microl/h) for 5 days was done to examine the development of morphine tolerance in male Sprague-Dawley rats. Noxious radiant heat was applied to the hindpaw and we measured the thermal withdrawal latency. To clarify the role of the group III mGluRs, an intrathecal group III mGluRs agonist (ACPT-III) or saline was administered to the morphine tolerant rats and we observed the change of the thermal withdrawal latency at 15, 30, 60, 90 and 120 min after delivery of ACPT-III. RESULTS: A continuous intrathecal infusion of morphine significantly increased the thermal withdrawal latency, as compared with the saline infused rats on day 1, with a decline on day 3 and the increase of withdrawal latency totally disappeared on day 5 (tolerance). Intrathecal ACPT-III increased the thermal withdrawal latency in the morphine tolerance rats. CONCLUSIONS: These results suggest that the group III mGluRs may be involved in the suppression of tolerance to morphine-induced antinociception at the spinal level.

The effect of inducing morphine tolerance on anti-allodynic action of gabapentin in spinal nerve-ligated rat / 대한마취과학회지

BACKGROUND: Morphine is more effective in inflammatory or acute pain than neuropathic pain. Recently, some reports demonstrated that the development and maintenance of opioid tolerance and neuropathic pain have similar aspects. Here, we evaluated whether morphine tolerance affects the anti-allodynic effect of gabapentin in spinal-nerve ligated rat. METHODS: Male Sprague-Dawley rats weighing 100-120 g received L5,6 spinal nerve ligation to induce neuropathic pain. Rats showing allodynia were implanted with intrathecal (i.t.) catheter to administer the experimental drugs into the subarachnoid space. To induce olerance to morphine, 15 microgram of morphine was injected via i.t. catheter twice a day for 7 days, and the effect of i.t. gabapentin on the paw withdrawal threshold was examined using the von Frey test before and after the development of morphine tolerance. RESULTS: Ligation of spinal nerves decreased the paw withdrawal threshold. Intrathecal morphine initially increased the paw withdrawal threshold, but this effect decreased gradually over time. However, morphine tolerance did not influence the effect of gabapentin on withdrawal threshold. CONCLUSIONS: Morphine tolerance did not affect gabapentin efficacay in a neuropathic pain model.

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.

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.

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 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.