A pharmacological study of slowly adapting mechanoreceptors responsive to cold thermal stimulation.

Weber's silver Thaler illusion is the perception that cold objects appear heavier than warm objects. We were interested in studying the pharmacology of mechanoreceptor units that displayed increased spontaneous firing to cold stimuli. An isolated rat sinus hair preparation with intact nerve terminals was used to record the activity of two types of slowly adapting mechanoreceptors (St I and St II) during temperature ramps (0.91-1.73 degrees C/min) from normal bath temperature of 31+/-2 degrees C, cold to 14.5 degrees C and heat to 46 degrees C. Twenty-seven of the 43 mechanoreceptor units displayed marked increases in their spontaneous firing to cold or cooling thermal gradients, and were classified as cold mechanoreceptors. A high proportion (3:1) of St II units were responsive to cold than not, while the ratio was reversed for St I units (1:2). Most cold mechanoreceptor units showed decreases in mechanical responses to cold thermal gradients. Similar to specific cold thermoreceptors, many of the cold mechanoreceptor units briefly displayed increased spontaneous firing at higher (>41 degrees C) temperatures. The spontaneous firing of cold mechanoreceptor units was increased by the transient receptor potential (TRP) channel agonist icilin (30-100 microM) in a dose-dependent manner. Responses to mechanical stimulation were generally unaffected by icilin in these units, although their evoked response latencies were significantly reduced (similar to the effect of K+ channel blocker tetraethylammonium in St II units). TRPM8 channel agonist, (-) menthol 200 microM, had mixed effects on spontaneous firing but consistently enhanced cold responses. Other TRP agonists, cinnamaldehyde 1-2 mM and camphor 0.5-2 microM, reduced spontaneous and evoked responses. TRPA1 agonist allyl isothiocyanate (mustard oil) 50-100 microM and TRPV1 agonist capsaicin 1-3 microM had no effect. A broad spectrum TRP antagonist, Ruthenium Red 30 microM, had no effect. The TRPM8 antagonist, capsazepine 100-200 microM, blocked cold-evoked responses. Although these data generally provide support for the possibility that cooling responses are mediated by TRPM8 channels, the detailed profile of results suggests that another, as yet unidentified TRP channel, is involved. Multiplex coding of mechanical and thermal information by slowly adapting mechanoreceptors may play a functional role in thermal perception, and may explain Weber's silver Thaler illusion.