The Role of Chemokine Signaling in Models of Peripheral Neuropathic PainPublic Deposited
Peripheral neuropathic pain is a debilitating affliction for which there is little effective treatment. Patients suffer from symptoms ranging from loss of sensation to hyperalgesia and allodynia. The neuroinflammatory process in chronic pain conditions has become a main focus of study because of the release of proinflammatory cytokines, which can lead to painful symptoms. Recently, studies have begun to focus on the role of chemokines in the genesis and maintenance of pain. Chemokines are known to mediate leukocyte migration, which is part of the inflammatory response associated with nociception. One recent study found that during chronic compression of the dorsal root ganglia (DRG), there is an upregulation of the CCR2 chemokine receptor and its ligand, MCP1, in the compressed neurons(White, Sun et al. 2005). Additionally, injection of chemokines into rodents' paws results in hyperalgesia (Oh, Tran et al. 2001). Evidence that chemokines are involved in neuropathic pain exists, however questions such as the receptors involved, the localization of chemokine expression and the order of events are still unanswered. The purpose of these studies was to explore the role of chemokines and their receptors in the mechanism of peripheral neuropathic pain in vivo. To do this, I compared and contrasted the role of chemokines and their receptors in three models of peripheral neuropathy including, a demyelinating peripheral neuropathy, and a neuropathy induced by the anti-retroviral therapy used in AIDS treatment, with and without a component of the HIV1 virus. A combination of animal behavior, in situ hybridization, mmunohistochemisty, transgenic mice and calcium imaging was used to analyze chemokine signaling in these models. It was found that in all pain models studied, chemokine signaling was upregulated in the neurons and glia of the DRG. The upregulation was seen in a subset of neurons that express the IB4 and TRPV1 proteins. Furthermore, chemokines played a role in the maintenance rather than the genesis of peripheral neuropathy. This data was confirmed when the use of antagonists to the receptors was effective in attenuating pain behavior at later time points. These results suggest that chemokine receptors are potential therapeutic targets for neuropathic pain treatment.