The effects of sympathetic outflow on upregulation of vanilloid receptors TRPV1 in primary afferent neurons evoked by intradermal capsaicin

Abstract

The vanilloid receptor TRPV 1 is a key nociceptive molecule located in primary afferent nociceptive neurons in dorsal root ganglia (DRG) for initiating neurogenic inflammation and pain. Our recent study demonstrates that up-regulation of TRPV 1 receptors by intradermal injection of capsaicin is modulated by activation of the protein kinase C (PKC) cascade. Neurogenic inflammation and pain resulting from capsaicin injection are sympathetically dependent, responding to norepinephrine, adenosine 5′-triphosphate (ATP) and/or neuropeptide Y released from sympathetic efferents. In a rat model of acute neurogenic inflammatory pain produced by capsaicin injection, we used immunofluorescence and Western blots combined with pharmacology and surgical sympathectomies to analyze whether the capsaicin-evoked up-regulation of TRPV 1 in DRG neurons is affected by sympathetic outflow by way of activating the PKC cascade. Sympathetic denervation reduced significantly the capsaicin-evoked expressions of TRPV 1 , calcitonin gene-related peptide and/or phosphorylated PKC and their co-expression. These reductions could be restored by exogenous pretreatment with an analog of ATP, α,β-methylene ATP. Inhibition of PKC with chelerythrine chloride prevented the ATP effect. Consistent results were obtained from experiments in which capsaicin-evoked changes in cutaneous inflammation (vasodilation and edema) were examined after sympathetic denervation, and the effects of the above pharmacological manipulations were evaluated. Our findings suggest that the capsaicin-evoked up-regulation of TRPV 1 receptors in DRG neurons is modulated sympathetically by the action of ATP released from sympathetic efferents to activate the PKC cascade. Thus, this study proposes a potential new mechanism of sympathetic modulation of neurogenic inflammation.

Profound alteration in cutaneous primary afferent activity produced by inflammatory mediators

“…Mechanically insensitive heat nociceptors express TRPV1 (Lawson et al, 2008) and release neuropeptides via local axon reflex that are involved in heat-induced vasodilation (Cavanaugh et al, 2011; Magerl and Treede, 1996; Rukwied et al, 2007; Xu et al, 2010). However, simply activating TRPV1 in these cells via brief noxious heat application by itself did not convert 'silent' afferents, indicating that heat and local vasodilation play a largely permissive role.…”

Conditioning pain stimulation does not affect itch induced by intra-epidermal histamine pricks but aggravates neurogenic inflammation in healthy volunteers

“…A stronger correlation was observed between the CPM-mediated increase in histaminergic neurogenic inflammation and the CPM-induced increase in skin conductance at the fingertips indicating that activity of efferent sudomotor fibers (tightly associated with sympathetic vasoconstrictor fibers) predicts CPM-induced neurogenic flare aggravation. This notion is theoretically supported by several animal studies wherein sympathectomy and pharmacological blockade of sympathetic efferent results in greatly diminished neurogenic inflammatory responsiveness (Levine et al 1986;Wang et al 2004;Xu et al 2010). Of particular interest, it has been shown that capsaicin-induced neurogenic flare in mice was dependent on sympathetic efferents by an indirect mechanism acting on peripheral a 1 -adrenoceptors, hereby augmenting sensitization of sensory afferents known to produce neurogenic inflammation (Ali et al 1999;Wang et al 2004).…”

Noradrenaline regulates substance P release from rat dorsal root ganglion neurons in vitro

“…Recent research has shown that sympathetic denervation signifi cantly reduces the CAP-evoked expression of tran- sient receptor potential vanilloid type 1 and sensory neuropeptide calcitonin gene-related peptide [21] . This suggests that sympathetic noradrenergic modulation is implicated in CAP-evoked pain sensitivity.…”

“…A previous study has shown that the α1-adrenoreceptor agonist phenylephrine causes the release of SP from terminals of CAP-sensitive sensory neurons in the lumbar enlargement of the dorsal spinal cord and urinary bladder [5] . Neurogenic infl ammation and pain resulting from CAP injection respond to NA released from sympathetic efferents [21] .…”