Spinal gene expression profiling and pathways analysis of a CB2 agonist (MDA7)-targeted prevention of paclitaxel-induced neuropathy.

AIMS: Patients receiving paclitaxel often develop peripheral neuropathies. We found that a novel selective cannabinoid CB2 receptor agonist (MDA7) prevents paclitaxel-induced mechanical allodynia in rats and mice. Here we investigated gene expression profiling in the lumbar spinal cord after 14-day treatment of MDA7 in paclitaxel animals and analyzed possible signaling pathways underlying the preventive effect of MDA7 on paclitaxel-induced neuropathy. METHODS: Peripheral mechanical allodynia was induced in rats or mice receiving intraperitoneal (i.p.) injection of paclitaxel at a dose of 1mg/kg daily for four consecutive days. MDA7 was administered at a dose of 15mg/kg 15min before paclitaxel and then continued daily for another 10days. Whole-genome gene expression profiling in the lumbar spinal cord of MDA7 and paclitaxel-treated rats was investigated using microarray analysis. The Ingenuity pathway analysis was performed to determine the potential relevant canonical pathways responsible for the effect of MDA7 on paclitaxel-induced peripheral neuropathy. RESULTS: We observed that the inflammatory molecular networks including tumor necrosis factor (TNF), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), transforming growth factor beta (TGFß), and mitogen-activated protein kinases (MAPK) signaling are most relevant to the preventive effect of MDA7 on paclitaxel-induced peripheral neuropathy. In addition, genes encoding molecules that are important in central sensitization such as glutamate transporters and N-methyl-d-aspartate receptor 2B (NMDAR2B), and neuro-immune-related genes such as neuronal nitric oxide synthase (nNOS1), chemokine CX3CL1 (a mediator for microglial activation), toll-like receptor 2 (TLR2), and leptin were differentially modulated by MDA7. CONCLUSION: The preventive effect of MDA7 on paclitaxel-induced peripheral allodynia in rats may be associated with genes involved in signal pathways in central sensitization, microglial activation, and neuroinflammation in the spinal cord.

MDA7: a novel selective agonist for CB2 receptors that prevents allodynia in rat neuropathic pain models.

BACKGROUND AND PURPOSE: There is growing interest in using cannabinoid type 2 (CB(2)) receptor agonists for the treatment of neuropathic pain. In this report, we describe the pharmacological characteristics of MDA7 (1-[(3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl)carbonyl]piperidine), a novel CB(2) receptor agonist. EXPERIMENTAL APPROACH: We characterized the pharmacological profile of MDA7 by using radioligand-binding assays and in vitro functional assays at human cannabinoid type 1 (CB(1)) and CB(2) receptors. In vitro functional assays were performed at rat CB(1) and CB(2) receptors. The effects of MDA7 in reversing neuropathic pain were assessed in spinal nerve ligation and paclitaxel-induced neuropathy models in rats. KEY RESULTS: MDA7 exhibited selectivity and agonist affinity at human and rat CB(2) receptors. MDA7 treatment attenuated tactile allodynia produced by spinal nerve ligation or by paclitaxel in a dose-related manner. These effects were selectively antagonized by a CB(2) receptor antagonist but not by CB(1) or opioid receptor antagonists. MDA7 did not affect rat locomotor activity. CONCLUSION AND IMPLICATIONS: MDA7, a novel selective CB(2) agonist, was effective in suppressing neuropathic nociception in two rat models without affecting locomotor behaviour. These results confirm the potential for CB(2) agonists in the treatment of neuropathic pain.