Infection, Pain, and Itch (1)

pain or itch, behavioral mechanisms, these sensations are mediated by nociceptor and pruriceptor neurons, respectively. Nociceptor neurons actively participate in the detection of pathogens by the host and the regulation of inflammation. Nociceptor and pruriceptor neurons also express specific pathogen-recognition mechanisms, including Toll-like receptors (TLRs), formyl peptide receptors (FPRs), and signaling pathways that sensitize transient receptor potential (TRP) channels.

Pain and Bacterial Infection

Bacterial pathogens often produce pain during host invasion, mediating painful infections of the skin, soft tissues, oral cavity, gastrointestinal (GI) tract, and genitourinary tract. Nociceptor neurons are able to detect gram-positive and gram-negative bacterial ligands through specific molecular pathways including TLRs and the FPR1, TRPA1, and TRPV1 ion channels.

Lipopolysaccharide (LPS)

Immune cells detect LPS through a pattern-recognition receptor complex consisting of TLR4, CD14 (cluster of differentiation 14), and MD2 (myeloid differentiation factor-2). TRPV1-positive trigeminal neurons express both TLR4 and CD14, allowing nociceptor neurons to directly sense LPS during infection. Neuronal application of LPS derived from P. gingivalis sensitizes nociceptor responses to capsaicin, the prototypic ligand for TRPV1. LPS sensitizes capsaicin-induced Ca2? influx and inward currents, as well as the release of the inflam- matory neuropeptide CGRP (calcitonin gene-related pep- tide), and this is abrogated by treatment of neurons with a TLR4 antagonist. Thus, LPS directly sensitizes nociceptors and produces pain sensitivity in tooth and gum decay. The establishment of pain by E. coli also depends on TRPV1. LPS induces Ca2+ flux in nociceptor neurons that is independent of TLR4, but depends on the TRPA1 ion channel. LPS is able to sensitize nociceptor neurons through TLR4-mediated sensitization of the TRPV1 ion channel or through direct gating of the TRPA1 ion channel

Immune-Mediated Mechanisms of Pain

The immune system plays an important role in pain sen- sitization during tissue inflammation. Upon activation by pathogen-derived ligands, immune cells secrete cytokines such as IL-1b, IL-6, and TNF-a, which are able to decrease the threshold for firing action potentials. Immune cells are also a major source of histamine and bradykinin as well as inflammatory lipids including prostaglandins (e.g. PGE2) and leukotrienes that are all potent sensitizers of nociceptor neurons and inflammatory pain.

Itch and Toll-Like Receptors

Pruriceptor neurons express TLR3, which recognizes double-stranded RNA, and TLR7, which rec- ognizes single-stranded RNA. The TLR7 ligand imiquimod induces inward currents in TRPV1-positive neurons and induces itch when injected into the cheek of mice. TLR3 agonist Poly I:C induces the firing of action potentials in DRG neurons and acute itch when injected into mice. Intrathecal injection of TLR4 antagonists decreases chronic itch, and this is partially mediated by their action on astrocytes. TLR4 expressed by pruriceptor neurons potentiates itch by the sensitization of TRPV1 and histamine responses.

1. I. M. Chiu, Infection, Pain, and Itch. Neurosci. Bull. 34, 109–119 (2018).