Elastoviscous substances with analgesic effects on joint pain reduce stretch-activated ion channel activity in vitro

Activation by noxious mechanical stimuli of sensory nerve fibres that signal joint pain takes place through stretch-activated ion channels, which open in response to increased membrane tension. It has been suggested that the analgesic effect of hyaluronan solutions used for intra-articular treatment of joint pain in humans are mediated by a reduction of the sensitivity of mechanosensory ion channels of nociceptive nerve terminals. We have investigated whether cross-linked hyaluronan solutions (hylans) of different elastoviscosities modify the response characteristics of stretch-activated ion channels of Xenopus laevis oocytes. Patch-clamp recordings on intact oocytes and in excised membrane patches (outside-out and inside-out configurations) were performed in Barth's solution (control condition) and after exposure to hylans of different elastoviscosities. For mechanical stimulation, monitored suction was applied through the microelectrode and the activity of stretch-activated channels was recorded. The activity of stretch-activated channels was significantly reduced in the presence of high elastoviscous hylan A (0.8% polymer content, molecular weight 6M) and of a mixture of hylan A (90% by weight) and hylan B (10% by weight), 0.9% total polymer content, a clinically used hylan product. In contrast, solutions of hylan A with the same chemical composition but reduced elastoviscosity (0.8% polymer content, molecular weight 96000) were found ineffective. It is concluded that stretch-activated channels have a decreased mechanical sensitivity in the presence of elastoviscous solutions of hylan, but not in the presence of non-elastoviscous solutions of hylan of the same concentration. These data suggest that the analgesic effects of intra-articular injections of elastoviscous solutions of hylans are due to a reduction of the sensitivity to mechanical forces of stretch-activated channels present in the membrane of joint mechanonociceptors.