LPS Sensitizes TRPV1 via Activation of TLR4 in Trigeminal Sensory Neurons

Abstract

Recent studies have demonstrated that the lipopolysaccharide (LPS) receptor (TLR4) is expressed in TRPV1 containing trigeminal sensory neurons. In this study, we evaluated whether LPS activates trigeminal neurons, and sensitizes TRPV1 responses via TLR4. To test this novel hypothesis, we first demonstrated that LPS binds to receptors in trigeminal neurons using competitive binding. Second, we demonstrated that LPS evoked a concentration-dependent increase in intracellular calcium accumulation (Ca(2+))(i) and inward currents. Third, LPS significantly sensitized TRPV1 to capsaicin measured by (Ca(2+))(i), release of calcitonin gene-related peptide, and inward currents. Importantly, a selective TLR4 antagonist blocked these effects. Analysis of these data, collectively, demonstrates that LPS is capable of directly activating trigeminal neurons, and sensitizing TRPV1 via a TLR4-mediated mechanism. These findings are consistent with the hypothesis that trigeminal neurons are capable of detecting pathogenic bacterial components leading to sensitization of TRPV1, possibly contributing to the inflammatory pain often observed in bacterial infections.

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

“…One possible link is by Toll-like receptors. TRPV1-positive trigeminal ganglion and DRG neurons are known to express Toll-like receptor-4 (Diogenes et al, 2011), which might be activated by fatty acids in the presence of nutrient excess. Another possible connection is oxidative stress.…”

Transient Receptor Potential Channels in Intestinal Inflammation: What Is the Impact of Cigarette Smoking?

“…For example, it has been shown that the function of TRPV1 in trigeminal neurons innervating the oral cavity can be modulated by the presence of endotoxin (lipopolysaccharide, LPS), an abundant outer wall glycolipid of Gram-negative bacteria [81]. Sensory neurons innervating the oral mucosa that express CGRP and TRPV1 also express immune receptors, such as the LPS receptor, Toll-like receptor 4 (TLR4) [81,82,83,84]. It has been reported that LPS as such cannot activate TRPV1 [81], but can increase the neuronal sensitivity towards TRPV1 agonists, yielding an increased release of CGRP (fig.…”

“…Sensory neurons innervating the oral mucosa that express CGRP and TRPV1 also express immune receptors, such as the LPS receptor, Toll-like receptor 4 (TLR4) [81,82,83,84]. It has been reported that LPS as such cannot activate TRPV1 [81], but can increase the neuronal sensitivity towards TRPV1 agonists, yielding an increased release of CGRP (fig. 2) [81,82].…”

“…It has been reported that LPS as such cannot activate TRPV1 [81], but can increase the neuronal sensitivity towards TRPV1 agonists, yielding an increased release of CGRP (fig. 2) [81,82]. CGRP not only increases neuronal sensitivity in the gut [84], but also has an anti-inflammatory role by binding to the CGRP receptor, which is expressed by immune cells, leading to a downregulation of TNF-α production by macrophages [85] and dendritic cells (DCs) [86].…”

TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

“…Of interest, TLR2, TLR3, and TLR4 contribute to the development of nerve injury-induced neuropathic pain by inducing glial activation and expression of proinflammatory cytokines in the spinal cord (7)(8)(9). Although TLRs are typically expressed by immune and glial cells, increasing evidence indicates that primary sensory neurons also express TLRs (e.g., TLR3, TLR4, TLR9) (10)(11)(12). But the functions of these TLRs in sensory neurons are largely unknown.…”