Adverse Modulation of the Firing Patterns of Cold Receptors by Volatile Anesthetics Affecting Activation of TRPM8 Channels: a Modeling Study

Transient receptor potential melastatin 8 channels (TRPM8s) are molecular sensors of temperature. They are expressed in primary afferent neurons (PANs) and function as receptors of innocuous cold. Depolarization of sensory endings of PANs by cooling-induced TRPM8 current is transduced into patterns of action potentials, encoding information about temperature and conveying it to the CNS, where an adequate thermoregulatory central response is generated. Under certain conditions, the receptor coding may appear misleading; e.g., selective activation of TRPM8 by agonists (menthol, icilin, or eucalyptol) elicits a coolness sensation in the absence of actual cooling. Both binding of such "cool mimetics" and physical cooling exert a similar effect on TRPM8s; the factor induces a hyperpolarization shift and generation of spiking patterns reporting about cooling of the environment and, thus, conveying false information in the former case. Application of volatile anesthetics (VAs) was recently shown to produce a similar shift of TRPM8 activation. This effect was assumed to underlie the adverse effects of VAs, such as shivering and a cooling sensation at the beginning of anesthesia, even at warm temperatures in the surgery theater. To validate this assumption, the VA effects on the activity patterns of the cool receptor should be investigated. Here, we upgraded an established model of the thermoreceptor by incorporating a prototype-based mechanism of VA-induced TRPM8 activation. On this model, we compared the activity patterns generated by the receptor at real cooling (VA-) and the VA-induced ("false") activation of TRPM8 (VA+). We demonstrated that, when affected by VA at a neutral (warm) temperature, the cold receptor activity switches from tonic singlet spiking to doublet bursting. We demonstrated that, under both conditions, VA- and VA+, along with cooling the receptor model exhibits a sequence of transitions between different patterns of impulse activities, single-spike, doublet, triplet, and quadruplet spiking. The VA+ receptor model is specifically characterized by starting these transitions earlier and completing the sequence in a narrower range and at a higher temperature. The average spiking rate of the VA+ receptor model was notably higher than that in the VA- one, and bursting patterns included greater numbers of spikes for any given coded temperature.