Mechanisms of paresthesiae, dysesthesiae, and hyperesthesiae: Role of Na+ channel heterogeneity

Paresthesiae, dysesthesiae, and hyperesthesiae ('positive symptoms') result from ectopic nerve impulses secondary to inappropriate membrane excitability which develops in the setting of chronic sensory axonal injury. The molecular changes in the membranes of dorsal root ganglion neurons which underlie ectopic impulse generation as a result of chronic axonal injury are unknown. Preliminary evidence has suggested that voltage-dependent Na+ channels are one of the participants in the production of ectopic impulses, but the precise form of their participation remains to be determined. The present paper reviews normal sensory anatomy and Na+ channel physiology, as well as clinical syndromes heralded by positive sensations and what is so far known about the cellular and molecular mechanisms underlying them. Properties of two distinct populations of Na+ channels native to the DRG neurons which give rise to cutaneous afferents are described. The biophysical properties of each population of Na+ channels must be tuned with respect to the other in order to cooperate in the generation of action potential activity underlying normal sensory function. A novel hypothesis is put forth suggesting that chronic axonal injury leads to intraneuronal heterogeneity of the populations of Na+ channels in cutaneous afferents, as revealed by their characteristic properties. This may result in one population of Nat channels activating the other, leading to membrane instability, and possibly to ectopic impulse generation.