MECHANISMS OF PARESTHESIAE, DYSESTHESIAE, AND HYPERESTHESIAE - ROLE OF NA+ CHANNEL HETEROGENEITY

Paresthesiae, dysesthesiae, and hyperesthesiae ('positive symptoms') r esult from ectopic nerve impulses secondary to inappropriate membrane excitability which develops in the setting of chronic sensory axonal i njury. The molecular changes in the membranes of dorsal root ganglion neurons which underlie ectopic impulse generation as a result of chron ic axonal injury are unknown. Preliminary evidence has suggested that voltage-dependent Na+ channels are one of the participants in the prod uction of ectopic impulses, but the precise form of their participatio n remains to be determined. The present paper reviews normal sensory a natomy and Na+ channel physiology, as well as clinical syndromes heral ded 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 ea ch population of Na+ channels must be tuned with respect to the other in order to cooperate in the generation of action potential activity u nderlying normal sensory function. A novel hypothesis is put forth sug gesting that chronic axonal injury leads to intraneuronal heterogeneit y of the populations of Na+ channels in cutaneous afferents, as reveal ed by their characteristic properties. This may result in one populati on of Nat channels activating the other, leading to membrane instabili ty, and possibly to ectopic impulse generation.