Temperature-dependent double spikes in C-nociceptors of neuropathic pain patients

Abstract

Five patients with small-fibre neuropathy characterized by temperature-dependent spontaneous pain, hyperalgesia/allodynia and signs of neurogenic inflammation were studied clinically and thermographically, and by microneurography. Thermography revealed hyperthermia confined to painful and hyperalgesic skin of distal extremities, in absence of sympathetic vasomotor denervation. Quantitative sensory testing documented either reduced thresholds or increased suprathreshold magnitude for heat pain. Microneurography identified 13 primary cutaneous C-nociceptors generating abnormal impulses in response to electrical stimuli and, in one patient, nociceptors firing spontaneously. All five patients showed examples of double spikes, in which a single brief electrical stimulus occasionally or regularly evoked two impulses. In one case, a second impulse occurred at one of three different delays. In all five patients, warming of the skin increased the probability of a second impulse occurring. Impulse doubling has previously been reported as occurring rarely in normal subjects and is attributable to unfiltering of multiple orthodromic impulses due to unidirectional conduction failure at branch points. A higher incidence of double firing in neuropathic pain patients is probably due to a reduced safety factor for conduction in the terminal arborizations of their C-nociceptors. These observations show that unidirectional conduction block provides a peripheral mechanism of temperature-dependent nociceptor hyperactivity in small-fibre neuropathy that may contribute to hyperalgesia.