Activin Induces Tactile Allodynia and Increases Calcitonin Gene-Related Peptide after Peripheral Inflammation

Abstract

Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide important in inflammatory pain that conveys pain information centrally and dilates blood vessels peripherally. Previous studies indicate that activin A increases CGRP-immunoreactive (IR) sensory neurons in vitro, and following wound, activin A protein increases in the skin and more neurons have detectable CGRP expression in the innervating dorsal root ganglion (DRG). These data suggest some adult sensory neurons respond to activin A or other target-derived factors with increased neuropeptide expression. This study was undertaken to test whether activin contributes to inflammatory pain and increased CGRP and to learn which neurons retained plasticity. After adjuvant-induced inflammation, activin mRNA, but not NGF or glial cell line-derived neurotrophic factor, increased in the skin. To examine which DRG neurons increased CGRP immunoreactivity, retrograde tracer-labeled cutaneous neurons were characterized after inflammation. The proportion and size of tracer-labeled DRG neurons with detectable CGRP increased after inflammation. One-third of CGRP-IR neurons that appear after inflammation also had isolectin B4 binding, suggesting that some mechanoreceptors became CGRP-IR. In contrast, the increased proportion of CGRP-IR neurons did not appear to come from RT97-IR neurons. To learn whether central projections were altered after inflammation, CGRP immunoreactivity in the protein kinase C␥-IR lamina IIi was quantified and found to increase. Injection of activin A protein alone caused robust tactile allodynia and increased CGRP in the DRG. Together, these data support the hypothesis that inflammation and skin changes involving activin A cause some sensory neurons to increase CGRP expression and pain responses.

Transforming Growth Factor-β1 Regulates Cdk5 Activity in Primary Sensory Neurons

“…In support of our proposal that TGF-␤1 plays a positive role in inflammation-induced hyperalgesia, activin A, another member of the TGF-␤ family, is released during peripheral inflammation. This increases the expression of the calcitonin generelated peptide and pain sensation (49). In addition, it was found that activin A mediates hyperalgesia through a mechanism involving acute sensitization of TRPV1 (50).…”

Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide

“…To investigate increase in CGRP release during tumor growth, we determined the mRNA levels of pro-CGRP, a precursor of CGRP, in DRGs (L 1-5 ) in tumorbearing WT because CGRP was reported to be up-regulated, and the pro-CGRP mRNA levels in the DRGs rose in the case of peripheral inflammation (24,25). As Fig.…”

“…These findings suggested that tumor implantation up-regulated pro-CGRP in the DRGs innervating the area of implantation and increased CGRP release and that CGRP was synthesized in the neuronal systems and was delivered to the periphery of the nerves innervating the sites where tumors grow. When inflammation was induced, CGRP was reported to be up-regulated, and the pro-CGRP mRNA levels in the DRGs that innervate the sites of inflammation rose (24,25). This may have been caused by the increased release of CGRP that was stimulated by the implanted tumors.…”

Activin Acutely Sensitizes Dorsal Root Ganglion Neurons and Induces Hyperalgesia via PKC-Mediated Potentiation of Transient Receptor Potential Vanilloid I

“…Each trial was repeated five times at 4 min intervals, and the PWL is the average of the five responses. Responses to mechanical stimulation in mice were assessed using calibrated von Frey filaments using the up-down paradigm as previously performed for assessment of tactile allodynia in rats (Xu et al, 2005).…”

“…Recent evidence suggests that activin itself causes both acute and prolonged tactile allodynia in vivo (Xu et al, 2005). Activin has been shown to increase expression of calcitonin-gene related peptide (CGRP) (Ai et al, 1999;Cruise et al, 2004), a peptide marker of the major subset of peripheral nociceptors that may contribute to the prolonged phase of hyperalgesia (Urban et al, 1994).…”