Jin Hua Cui

Antinociceptive effect of intrathecal cannabinoid receptor agonist WIN 55,212-2 in a rat bone tumor pain model

Bone tumor pain is a poorly controlled pain comprising background and severe pain on moving or weight-bearing postures that decreases the quality of life for cancer patients; thus, more effective analgesics are clearly needed. This study evaluated the efficacy of a cannabinoid (CB) receptor agonist (WIN 55,212-2) on bone tumor pain in the spinal cords of rats, and clarified the roles of the CB1 and CB2 receptors in WIN 55,212-2-induced antinociception at the spinal level. Bone tumor pain was induced by injecting MRMT-1 tumor cells (1×10(5)) into the right tibias of female Sprague-Dawley rats under sevoflurane anesthesia. Bone tumor development was monitored radiologically. Under sevoflurane anesthesia, a polyethylene catheter was inserted into the intrathecal space for drug administration. To assess pain, the withdrawal threshold was measured by applying a von Frey filament to the tumor cell inoculation site. The effect of intrathecal WIN 55,212-2 was investigated. Next, the WIN 55,212-2-mediated antinociception was reversed using CB1 (AM 251) and CB2 (AM 630) receptor antagonists. The intratibial injection of MRMT-1 tumor cells produced radiologically confirmed bone tumors. The paw withdrawal threshold decreased significantly (mechanical allodynia) with tumor development; however, intrathecal WIN 55,212-2 dose-dependently increased the withdrawal threshold. The antinociceptive effect of WIN 55,212-2 was reversed by both CB1 and CB2 receptor antagonists. Intrathecal WIN 55,212-2 reduced bone tumor-related pain behavior mediated via spinal CB1 and CB2 receptors. Therefore, spinal CB receptor agonists may be novel analgesics in the treatment of bone tumor pain.

The intrathecally administered kappa-2 opioid agonist GR89696 and interleukin-10 attenuate bone cancer-induced pain through synergistic interaction.

BACKGROUND:Although bone cancer–related pain is one of the most disruptive symptoms in patients with advanced cancer, patients are often refractory to pharmacological treatments; thus, more effective treatments for bone cancer pain are needed. We evaluated the analgesic efficacy of and interaction between intrathecal GR89696, a &kgr;2-opioid receptor agonist, and interleukin (IL)-10 in a rat model of bone cancer pain. METHODS:The rat model of bone cancer pain was produced by right tibia intramedullary injection of rat breast cancer cells, and an intrathecal catheterization was performed. Ten days later, a paw-withdrawal threshold to mechanical stimulus by von Frey hairs was measured using the up-down method, after intrathecal administration of GR89696 and IL-10. The interaction between the 2 drugs was also evaluated using an isobolographic analysis. RESULTS:Intrathecal GR89696 and IL-10 significantly increased the paw withdrawal threshold of the cancer cell–implanted rat, in a dose-dependent manner, with 50% effective dose values (95% confidence interval) of 50.78 &mgr;g (31.80–80.07&mgr;g) and 0.83 &mgr;g (0.59–1.15 &mgr;g), respectively. Isobolographic analysis revealed a synergistic interaction between intrathecal GR89696 and IL-10. CONCLUSIONS:Intrathecally administered GR89696 and IL-10 attenuated bone cancer–induced pain, and the 2 drugs interacted synergistically in the spinal cord. These results raise the intriguing possibility of &kgr;2-opioid receptor agonists and IL-10 as a new therapeutic approach for the management of bone cancer–associated pain.

Pharmacology of Cannabinoid Receptor Agonists and a Cyclooxygenase-2 Inhibitor in Rat Bone Tumor Pain

We evaluated the pharmacology of spinal selective cannabinoid (CB) receptor agonists and a cyclooxygenase-2 (COX-2) inhibitor on bone tumor pain. MRMT-1 tumor cells were injected into the tibia of female Sprague-Dawley rats. MRMT-1 tumor cells produced a bone tumor confirmed by radiologic and histological findings. Intrathecal CB1 (ACEA) and CB2 receptor (AM 1241) agonists and a COX-2 inhibitor (DuP 697) dose-dependently increased the withdrawal threshold. The calculated ED50 (nmol/l) values for ACEA, AM 1241 and DuP 697 were 0.007, 2.3 and 76.1, respectively. Reverse transcriptase polymerase chain reaction and Western blot showed that COX-2 mRNA and protein, but not CB1 or CB2 receptor, were increased in the spinal cords of rats with bone tumors. Spinal CB1 receptor and CB2 receptor agonists and COX-2 inhibitor may be useful in the management of bone tumor pain. Furthermore, CB2 receptor agonist may be more potent than CB1 receptor agonist and COX-2 inhibitor.

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 µL 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.

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

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.