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TRPA1 identified as new pain target in gram-negative bacterial infections
The transient potential receptor cation channel TRPA1 plays a key role in mediating pain and neurogenic inflammation caused by lipopolysaccharide in gram-negative infections, according to results of a recent study.
The study researchers analyzed these processes using a variety of approaches, including electrical recordings of primary sensory neurons, blockers of toll-like receptor 4 (TLR4) signaling, and behavioral evaluation in transgenic mice.
The researchers found that lipopolysaccharide (LPS) activates and depolarizes TRPA1-expressing nociceptors. They also discovered that LPS triggers TRPA1 channels in a membrane-delimited, excitatory manner, converting irritant stimuli into nociceptor activity.
Although the effects of LPS on neurogenic activity have generally been associated with activation of the TLR4 signaling pathway, the current study found that LPS exerted excitatory effects on sensory neurons isolated from TLR4 knock-out mice. The researchers also tested this effect through the use of CLI-095, a TLR4 signaling inhibitor. After 10 minutes of pretreatment with CLI-095, neuronal response to LPS was not significantly affected.
The study researchers determined that acute neuropeptide release and subsequent neurogenic inflammation by LPS is largely dependent on TRPA1 channels. However, TRPA1 channels were not found to be essential to systemic inflammatory response by LPS.
The researchers said their findings regarding the role of TRPA1 in LPS-induced neurogenic inflammation could potentially guide future treatment strategies.
“The identification of TRPA1 as a functional target for LPS may represent an important missing link between the stimulation of afferent sensory fibers and the immune responses during a bacterial challenge,” the researchers wrote. “Identification of TRPA1 as a new target for LPS opens novel avenues for the treatment of adverse biological responses of gram-negative bacterial infections.”
Disclosure: Meseguer and two other researchers are inventors on a patent (WO/2013/038046) held by the Universidad Miguel Hernández and Consejo Superior de Investigaciones Científicas, related to the use of TRPA1 antagonists for the treatment of symptoms caused by bacterial infections or bacterial endotoxins.