The long-term objective of this study is to determine how the growth factor artemin (Artn) causes thermal and chemical sensitization of sensory neurons under conditions of chronic inflammation. Artn expression is normally low but becomes significantly elevated in inflamed tissue. Mice that overexpress Artn in skin (ART-OE mice) or that are injected with Artn also exhibit behavioral sensitivity to heat, cold and chemical (capsaicin and mustard oil) stimuli. The ability of Artn to induce thermal and chemical sensitivity and its rise in inflamed tissue suggests that Artn signaling underlies a component of the hypersensitivity associated with inflammation. Analysis of sensory ganglia of ART-OE mice showed enhanced expression of TRPV1 and TRPA1 suggesting the activity of these channel receptors underlie at least some of the Artn-induced sensitization. However, new microarray profiling data of ART-OE ganglia showed a significant elevation in subunits of the nicotinic acetylcholine receptor (nAChR), suggesting Artn modulates the composition of nAChRs as well. We therefore propose to test the hypothesis that the thermal and chemical sensitivity exhibited by Artn-responsive GFR13-positive afferents reflects not only enhanced TRP responses but also enhanced activity of nAChRs. We propose three specific aims:
Aim 1 will use immunodetection assays to assess how Artn and inflammation affects translation and distribution of nAChR subunits in sensory afferents.
Aim 2 uses calcium imaging and patch-clamp protocols to determine the effect of Artn on functional properties of nAChRs in GFR13 afferents under normal and inflamed conditions.
Aim 3 will determine whether nAChR subunits contribute to inflammatory thermal hyperalgesia using a newly developed siRNA procedure that will reduce expression of specific nAChR subunits in peripheral neurons. In vivo assays will be used to determine if hypersensitivity induced by CFA injection can be reduced. These findings of Artn regulation of nAChR expression provide a new dimension for investigating the role of growth factors in sensory afferents and their role in the pathogenesis of inflammatory disease.
Local, non-neuronal production of neuro-active substances such as growth factors, acetylcholine, glutamate and peptides is commonly elevated in inflammatory diseases such as pancreatitis, psoriasis, rheumatoid arthritis and cystitis. Our findings suggest that the growth factor Artn is produced in inflamed tissue and that its production contributes to sensitization of a specific subpopulation of pain signaling neurons. We propose a mechanism by which Artn produces its effect that, if correct, may allow development of analgesic compounds that are effective in treating pain associated with chronic inflammatory disease.
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