No abstract

CB2 cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB2 receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB2 receptors in the normal CNS. To date, there has been virtually no information regarding the mechanism of CB2 receptormediated inhibition of pain responses. Here, we test the hypothesis that CB2 receptor activation stimulates release from keratinocytes of the endogenous opioid ␤-endorphin, which then acts at opioid receptors on primary afferent neurons to inhibit nociception. The antinociceptive effects of the CB2 receptor-selective agonist AM1241 were prevented in rats when naloxone or antiserum to ␤-endorphin was injected in the hindpaw where the noxious thermal stimulus was applied, suggesting that ␤-endorphin is necessary for CB2 receptor-mediated antinociception. Further, AM1241 did not inhibit nociception in -opioid receptordeficient mice. Hindpaw injection of ␤-endorphin was sufficient to produce antinociception. AM1241 stimulated ␤-endorphin release from rat skin tissue and from cultured human keratinocytes. This stimulation was prevented by AM630, a CB2 cannabinoid receptorselective antagonist and was not observed in skin from CB2 cannabinoid receptor-deficient mice. These data suggest that CB2 receptor activation stimulates release from keratinocytes of ␤-endorphin, which acts at local neuronal -opioid receptors to inhibit nociception. Supporting this possibility, CB2 immunolabeling was detected on ␤-endorphin-containing keratinocytes in stratum granulosum throughout the epidermis of the hindpaw. This mechanism allows for the local release of ␤-endorphin, where CB2 receptors are present, leading to anatomical specificity of opioid effects.␤-endorphin ͉ nociception ͉ pain ͉ keratinocyte ͉ skin C B 2 cannabinoid receptor-selective agonists are very promising candidates for the treatment of pain. Activation of CB 2 cannabinoid receptors inhibits nociception to thermal and mechanical stimuli (1, 2), thermal and tactile hypersensitivity produced by peripheral inflammation (2-4), and tactile and thermal hypersensitivity produced in a neuropathic pain model (5). Experimental findings suggesting that activation of peripheral (noncentral nervous system) CB 2 receptors is necessary and sufficient to inhibit pain responses come from site-specific injections of CB 2 receptor-selective agonists and antagonists (1, 3, 4). Importantly, CB 2 cannabinoid receptor-selective agonists do not cause central nervous system (CNS) effects (1, 6), consistent with the inability to demonstrate the expression of CB 2 receptors in the normal CNS (7-10). The lack of CNS effects is an important feature of this class of drug candidates because the efficacy of current pain therapies is frequently limited by CNS side effects. However, enthusiasm for this therapeutic approach has been tempered by the lack of information regarding the mechanism underlying the inhibition of n...

The prevailing view of the astrocytic response to injury is that reactive astrocytes impede the regenerative process by forming scar tissue. As the levels of many cytokines dramatically increase following CNS insult and as this increase in cytokine expression precedes the production of the glial scar, a longstanding view has been that cytokines diminish neuronal survival and regeneration by stimulating the formation of astrogliotic scar tissue. However, there is a wealth of data indicating that cytokines 'activate' astrocytes, and that cytokinestimulated astrocytes can promote the recovery of CNS function. Supporting evidence demonstrates that cytokine-activated astrocytes produce energy substrates and trophic factors for neurons and oligodendrocytes, act as free radical and excess glutamate scavengers, actively restore the blood-brain barrier, promote neovascularization, restore CNS ionic homeostasis, promote remyelination and also stimulate neurogenesis from neural stem cells. Accordingly, a re-assessment of cytokineactivated astrocytes is necessary. Here, we review studies that promote the thesis that cytokines elicit potent neuroprotective and regenerative responses from astrocytes. Keywords: ciliary neurotrophic factor, gliosis, interleukin-1, microglia. J. Neurochem. (2004) 89, 1092-1100. Astrocytes are the major support cells of the CNSAstrocytes are dynamic cells that maintain homeostasis in the undamaged CNS. Astrocytes express numerous receptors that enable them to respond to virtually all known neuroactive compounds, including neurotransmitters, neuropeptides, growth factors, cytokines, small molecules and toxins. These receptors enable astrocytes to not only participate in signal processing, but to function as sentinels. Astrocytes also establish and maintain CNS boundaries, including the blood-brain barrier (BBB) and the glial limitans, through interactions with endothelial and leptomeningeal cells. Given their important roles in establishing and maintaining CNS homeostasis, an adaptive response by astrocytes to tissue damage should be expected. Indeed, when astrocytes sense that the homeostasis of the brain or spinal cord has been disrupted, their metabolic activity increases, as well as their production of growth and trophic factors; thus endowing them with a greater capacity to protect other brain cells from energy depletion, toxic-free radicals, ammonia, metals and calcium overload. Additionally, after injury, cytokine-activated astrocytes promote the reformation of essential barriers and reestablishment of CNS ionic homeostasis.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disruptive and persistent side-effect of cancer treatment with paclitaxel. Recent reports showed that paclitaxel treatment results in the activation of Toll-like receptor 4 (TLR4) signaling and increased expression of monocyte chemotactic protein 1 (MCP-1) in dorsal root ganglion cells. In this study, we sought to determine whether an important consequence of this signaling and also a key step in the CIPN phenotype was the recruitment and infiltration of macrophages into dorsal root ganglia (DRG). Here, we show that macrophage infiltration does indeed occur in a time course that matches the onset of the behavioral CIPN phenotype in Sprague-Dawley rats. Moreover, depletion of macrophages by systemic administration of liposome-encapsulated clodronate (clophosome) partially reversed behavioral signs of paclitaxel-induced CIPN as well as reduced TNFα expression in DRG. Intrathecal injection of MCP-1 neutralizing antibodies reduced paclitaxel-induced macrophage recruitment into the DRG and also blocked the behavioral signs of CIPN. Intrathecal treatment with the TLR4 antagonist LPS-RS blocked mechanical hypersensitivity, reduced MCP-1 expression, and blocked the infiltration of macrophages into the DRG in paclitaxel treated rats. Finally, the inhibition of macrophage infiltration into DRG following paclitaxel treatment with clodronate or LPS-RS prevented the loss of intra-epidermal nerve fibers (IENFs) observed following paclitaxel treatment alone. Taken altogether, these results are the first to indicate a mechanistic link such that activation of TLR4 by paclitaxel leads to increased expression of MCP-1 by DRG neurons resulting in macrophage infiltration to the DRG that express inflammatory cytokines and the combination of these events results in IENF loss and the development of behavioral signs of CIPN.

Background: Most of Multiple Sclerosis (MS) patients without previous optic neuritis (ON) show