Nociceptive response to innocuous mechanical stimulation is mediated via myelinated afferents and NK-1 receptor activation in a rat model of neuropathic pain.
Peripheral nerve injury in humans can produce a persistent pain state characterized by spontaneous pain and painful responses to normally innocuous stimuli (allodynia). Here we attempt to identify some of the neurophysiological and neurochemical mechanisms underlying neuropathic pain using an animal model of peripheral neuropathy induced in male Sprague-Dawley rats by placing a 2-mm polyethylene cuff around the left sciatic nerve according to the method of Mosconi and Kruger. von Frey hair testing confirmed tactile allodynia in all cuff-implanted rats before electrophysiological testing. Rats were anesthetized and spinalized for extracellular recording from single spinal wide dynamic range neurons (L(3-4)). In neuropathic rats (days 11-14 and 42-52 after cuff implantation), ongoing discharge was greater and hind paw receptive field size was expanded compared to control rats. Activation of low-threshold sensory afferents by innocuous mechanical stimulation (0.2 N for 3 s) in the hind paw receptive field evoked the typical brief excitation in control rats. However, in neuropathic rats, innocuous stimulation also induced a nociceptive-like afterdischarge that persisted 2-3 min. This afterdischarge was never observed in control rats, and, in this model, is the distinguishing feature of the spinal neural correlate of tactile allodynia. Electrical stimulation of the sciatic nerve at 4 and at 20 Hz each produced an initial discharge that was identical in control and in neuropathic rats. This stimulation also produced an afterdischarge that was similar at the two frequencies in control rats. However, in neuropathic rats, the afterdischarge produced by 20-Hz stimulation was greater than that produced by 4-Hz stimulation. Given that acutely spinalized rats were studied, only peripheral and/or spinal mechanisms can account for the data obtained; as synaptic responses from C fibers begin to fail above approximately 5-Hz stimulation [Pain 46 (1991) 327], the afterdischarge in response to 20-Hz stimulation suggests a change mainly in myelinated afferents and a predominant role of these fibers in eliciting this afterdischarge. These data are consistent with the suggestion that peripheral neuropathy induces phenotypic changes predominantly in myelinated afferents, the sensory neurons that normally respond to mechanical stimulation. The NK-1 receptor antagonist, CP-99,994 (0.5 mg/kg, i.v.), depressed the innocuous pressure-evoked afterdischarge but not the brief initial discharge of wide dynamic range neurons, and decreased the elevated ongoing rate of discharge in neuropathic rats. These results support the concept that following peripheral neuropathy, myelinated afferents may now synthesize and release substance P. A result of this is that tonic release of substance P from the central terminals of these phenotypically altered neurons would lead to ongoing excitation of NK-1-expressing nociceptive spinal neurons. In addition, these spinal neurons would also exhibit exaggerated responses to innocuous pressure stimulation. The data in this study put forth a possible neurophysiological and neurochemical basis of neuropathic pain and identify substance P and the NK-1 receptor as potential neurochemical targets for its management.
Pitcher
Graham M
GM
Department of Physiology, McGill University, Montreal, Quebec, Canada H3G 1Y6.
Henry
James L
JL
D000344:Afferent Pathways / Q000502:physiology*; D000818:Animals; D003250:Constriction; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D004594:Electrophysiology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D007839:Functional Laterality; D006614:Hindlimb / Q000294:innervation / Q000502:physiology / Q000528:radiation effects; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000502:physiology*; D064729:Neurokinin-1 Receptor Antagonists; D010146:Pain / Q000145:classification / Q000209:etiology / Q000503:physiopathology*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000503:physiopathology; D010812:Physical Stimulation / Q000009:adverse effects; D010880:Piperidines / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D012584:Sciatic Nerve / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology / Q000528:radiation effects; D013997:Time Factors
D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine