Potentiation of the Transient Receptor Potential Vanilloid 1 Channel Contributes to Pruritogenesis in a Rat Model of Liver Disease

Abstract

Background:The etiology and neurophysiology of generalized pruritus associated with liver disease remain unknown. Results: Rats with bile duct ligation displayed enhanced scratching and thermal hyperalgesia dependent on PAR 2 activation and TRPV1 potentiation. Conclusion: Pruritus and hyperalgesia in BDL-rats are associated with neuroinflammation and involve PAR 2 -induced TRPV1 sensitization. Significance: Pharmacological modulation of PAR 2 and/or TRPV1 emerges as a potential therapeutic approach for liver pruritus refractory to conventional treatments.

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…PAR 2 -dependent sensitization of TRPV1 on sensory afferents is also proposed to be pruritogenic (Belghiti et al, 2013). However, itch induced by the PAR 2 activating peptide SLIGRL is potentially mediated by the MrgprC11, rather than PAR 2 .…”

“…The role of B 1 R and B 2 R activity in PAR 2 -dependent pruritus has also been investigated and suggests that kinin receptors function downstream of protease-induced pruritic responses (Costa et al, 2010). Although the bile acidbradykinin system has not been clearly defined, TRPV1 sensitization was recently demonstrated to contribute to liver disease-induced itch and is predicted to play a major role, potentially via receptors for bradykinin, histamine, serotonin, or PAR 2 (Belghiti et al, 2013). In addition, TRPV1 and TRPA1 are expressed in distinct and overlapping populations of peptidergic and IB4 + neurons (Bhattacharya et al, 2008;Kim et al, 2010), and coexpression of TRPA1 and TRPV1 on peptidergic C-fibers is hypothesized to result in Ca 2+ -dependent…”

“…However, these mice still exhibit scratching behavior, which suggests that alternate histamine-dependent pruritic pathways exist (Shim et al, 2007). Histamine receptor signaling can stimulate kinase activity and the production of sensitizing agents, such as prostaglandin PGE 2 , suggesting the involvement of other TRP-sensitizing pathways (Belghiti et al, 2013).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…However, the possibility could not be excluded that both mucunain and histamine target TRPV1 via different second messengers, PAR-2 and PLA 2 , respectively. Indeed, it was postulated that endogenous pruritogenic substances act on TRPV1 indirectly via PAR-2 activation, based a rat model of hepatogenic pruritus induced by bile duct ligation (Belghiti et al, 2013).…”

Methods for Preclinical Assessment of Antipruritic Agents and Itch Mechanisms Independent of Mast-Cell Histamine

“…39) Thus, there has been no report on pathological pruritus that is attributed to the increased activity of the opioid peptidergic systems in the central nervous system.…”