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Cytokines Modulate the Expression of Calcitonin‐Gene‐Related‐Peptide and Substance P in Primary Rat DRG Neuron‐glia Co‐cultures

In the peripheral nervous system, dorsal root ganglion (DRG) neurons are the primary sensory neuron responsible for the transmission of temperature, touch, proprioception and pain. Recently, there has been increased interest in the role of neuro‐immune interactions in peripherally‐mediated neuropathic pain. Activated immune cells that infiltrate DRG release a mixture of inflammatory mediators that play a role in the development and maintenance of pain. However, the relationship between immune cells, pro‐inflammatory mediators and sensory neurons in the development and maintenance of pain are not completely understood. In this study, we investigated the effects of the cytokines interferon gamma (IFNγ) and tumor necrosis factor‐alpha (TNFα), and the chemokine fractalkine on the expression of calcitonin‐gene‐related‐peptide (CGRP) and substance P (SP) in DRG neuron‐glia co‐cultures. IFNγ decreased CGRP and substance P expression while TNFα increased CGRP expression, preferentially in small and medium size neurons. IFNγ and TNFα, both also increased nitric oxide (NO) production in a concentration‐dependent manner, at concentrations that affected CGRP and SP expression. However, inhibitors of nitric oxide synthase (L‐NAME) and of IKKB/NFkB (TPCA‐1) did not alter TNFα effects on CGRP expression. The data from this study demonstrates that cytokines and chemokines differentially modulate the expression of CGRP and SP in DRG neurons. Understanding the regulation of these two key inflammatory neuropeptides may provide novel insights regarding the development of new and effective therapeutics for neuropathic pain.