Hyaluronan modulates TRPV1 channel opening, reducing peripheral nociceptor activity and pain

Abstract

Hyaluronan (HA) is present in the extracellular matrix of all body tissues, including synovial fluid in joints, in which it behaves as a filter that buffers transmission of mechanical forces to nociceptor nerve endings thereby reducing pain. Using recombinant systems, mouse-cultured dorsal root ganglia (DRG) neurons and in vivo experiments, we found that HA also modulates polymodal transient receptor potential vanilloid subtype 1 (TRPV1) channels. HA diminishes heat, pH and capsaicin (CAP) responses, thus reducing the opening probability of the channel by stabilizing its closed state. Accordingly, in DRG neurons, HA decreases TRPV1-mediated impulse firing and channel sensitization by bradykinin. Moreover, subcutaneous HA injection in mice reduces heat and capsaicin nocifensive responses, whereas the intra-articular injection of HA in rats decreases capsaicin joint nociceptor fibres discharge. Collectively, these results indicate that extracellular HA reduces the excitability of the ubiquitous TRPV1 channel, thereby lowering impulse activity in the peripheral nociceptor endings underlying pain.

Kunitz-Type Peptide HCRG21 from the Sea Anemone Heteractis crispa Is a Full Antagonist of the TRPV1 Receptor

“…These flexible extracellular loops were not determined experimentally but a pool of biochemical data evidenced its significance for TRPV1 responses on diverse stimuli [67,68]. Notably, these long extracellular loops that form TRPV1 pore turret and are directly linked to the channel pore helix represent a highly variable region among TRPV family members.…”

Extracellular matrix hyaluronan signals via its CD44 receptor in the increased responsiveness to mechanical stimulation

“…The relationship between changes in the ECM and the increase in the sensitivity of sensory neurons to stimulation has been investigated (Hucho and Levine, 2007; Jeske et al, 2009; Hu et al, 2010; Traverso, 2011; Kubo et al, 2012; Caires et al, 2015). Since the ECM can function as a storage depot for biologically active molecules, such as MCP-1 and tumor necrosis alpha (Edovitsky et al, 2006; Nasser, 2008; Goodall et al, 2014), and pathological conditions can release mediators that can contribute to changes in mechanical, or even thermal, sensitivity (Yamanaka et al, 2004; Li et al, 2012), the ECM can be considered to contribute to inflammatory pain, the integrity of the ECM playing a role in sensory neuron homeostasis (Li et al, 2012).…”

Use of Intraarticular Hyaluronic Acid in the Management of Knee Osteoarthritis in Clinical Practice

“…A recent review of the preclinical basic science literature performed by Altman et al highlighted the major role of HA binding to cluster of differentiation 44 receptors in this complex mechanism, as numerous of its mediated effects (e.g., inhibition of interleukin [IL]–1β, IL‐6, and matrix metalloproteinase [MMP] expression, and reduction in prostaglandin E 2 synthesis) contribute to the chondroprotection, proteoglycan/glycosaminoglycan synthesis, antiinflammatory, and subchondral effects as observed in vitro. Alternative pathways involving HA binding to intercellular adhesion molecule 1 and modulation of transient receptor potential vanilloid channel 1 activity have also been described. In addition, the toll‐like receptor (TLR) signaling pathway has been suggested to contribute to the antiinflammatory and anticatabolic (inhibition of inflammation‐induced activation of MMPs) effects of IAHA in joint tissues .…”