RESUMO
Intact and injured cutaneous C-fibers in the rat sural nerve are cold sensitive, heat sensitive, and/or mechanosensitive. Cold-sensitive fibers are either low-threshold type 1 cold sensitive or high-threshold type 2 cold sensitive. The hypothesis was tested, in intact and injured afferent nerve fibers, that low-threshold cold-sensitive afferent nerve fibers are activated by the transient receptor potential melastatin 8 (TRPM8) agonist menthol, whereas high-threshold cold-sensitive C-fibers and cold-insensitive afferent nerve fibers are menthol insensitive. In anesthetized rats, activity was recorded from afferent nerve fibers in strands isolated from the sural nerve, which was either intact or crushed 6-12 days before the experiment distal to the recording site. In all, 77 functionally identified afferent C-fibers (30 intact fibers, 47 injured fibers) and 34 functionally characterized A-fibers (11 intact fibers, 23 injured fibers) were tested for their responses to menthol applied to their receptive fields either in the skin (10 or 20%) or in the nerve (4 or 8 mM). Menthol activated all intact (n = 12) and 90% of injured (n = 20/22) type 1 cold-sensitive C-fibers; it activated no intact type 2 cold-sensitive C-fibers (n = 7) and 1/11 injured type 2 cold-sensitive C-fibers. Neither intact nor injured heat- and/or mechanosensitive cold-insensitive C-fibers (n = 25) and almost no A-fibers (n = 2/34) were activated by menthol. These results strongly argue that cutaneous type 1 cold-sensitive afferent fibers are nonnociceptive cold fibers that use the TRPM8 transduction channel.
Assuntos
Mentol/farmacologia , Fármacos do Sistema Nervoso Periférico/farmacologia , Nervo Sural/efeitos dos fármacos , Nervo Sural/fisiopatologia , Sensação Térmica/efeitos dos fármacos , Sensação Térmica/fisiologia , Anestesia , Animais , Temperatura Baixa , Estimulação Elétrica , Temperatura Alta , Masculino , Microeletrodos , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Estimulação Física , Ratos Wistar , Fenômenos Fisiológicos da Pele/efeitos dos fármacos , Nervo Sural/lesões , Canais de Cátion TRPM/agonistas , Canais de Cátion TRPM/metabolismoRESUMO
We hypothesized that cutaneous afferent myelinated fibers (A-fibers) and afferent unmyelinated fibers (C-fibers) respond to the same natural stimuli applied to their axons as to their terminals in the skin. In anesthetized rats, activity was recorded from afferent axons in strands isolated proximally from the sural nerve. Mechanical, cold or heat stimuli were applied to the skin or along a 15-mm length of the distal sural nerve. One-hundred and eighteen A-fibers and 109 C-fibers were characterized by their conduction velocity and/or shape of their action potentials, and by their responses to natural stimulation of the skin. Then, these fibers were tested for their responses to the same stimuli applied to the nerve. In some cases, the nerve was crushed distally after the nerve fibers had been characterized by their responses to physiological stimulation of the skin, and the responses to stimuli applied to the nerve proximal to the lesion were tested again. Almost all non-nociceptive cold-sensitive (type 1) C-fibers (97%) could be activated by cold stimuli applied to the nerve. Of nociceptive cold-sensitive (type 2) C-fibers, 39% were activated by cold stimuli applied to the nerve. Furthermore, 34% of heat-sensitive C-fibers could be activated by heating the nerve. In contrast, only 2-4% of mechanosensitive A-fibers and C-fibers responded to mechanical stimuli applied to the nerve. In conclusion, cold and heat sensitivity of cutaneous afferent neurons is not restricted to their terminals in the skin, but often extends along the axons in the nerve. Mechanosensitivity is restricted to the afferent endings in the skin.
Assuntos
Axônios/fisiologia , Mecanorreceptores/fisiologia , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Neurônios Aferentes/fisiologia , Termorreceptores/fisiologia , Sensação Térmica/fisiologia , Animais , Temperatura Baixa , Eletrofisiologia , Temperatura Alta , Masculino , Neurônios Aferentes/citologia , Estimulação Física , Ratos , Ratos Wistar , Pele/inervação , Nervo Sural/citologia , Nervo Sural/fisiologiaRESUMO
Lidocaine applied systemically or locally attenuates neuropathic pain in patients. Here we tested the hypothesis that ectopic activity in injured afferent A- or C-fibers is suppressed by lidocaine. In rats the sural nerve (skin nerve) or lateral gastrocnemius-soleus nerve (muscle nerve) was crushed. Four to 11 days after crush lesion afferent fibers were isolated from the lesioned nerves in bundles rostral to the injury site. Ongoing ectopic activity was recorded from 75 A-fibers (muscle N=43, skin N=32) and 69 C-fibers (muscle N=30, skin N=39). Most afferent fibers were functionally characterized by their responses to mechanical and thermal (mostly heat) stimuli applied at or distal to the nerve injury site. Low-threshold cold-sensitive cutaneous C-fibers were excluded from the analysis. Lidocaine was either applied to the nerve at or distal to the injury site in concentrations of 1 to 1000 µg/mL or injected i.v. in doses of 0.09 to 9 mg/kg (skin) or 0.047 to 4.7 mg/kg (muscle). Local application of lidocaine depressed ectopic activity in A- and C-fibers dose-dependently. Depression was weaker in C- than in A-fibers. Intravenous application of lidocaine depressed ongoing ectopic activity in A- and C-fibers dose-dependently. Responses to heat or mechanical stimulation of the injured nerve were not suppressed at the highest concentrations of lidocaine. The results support the hypothesis that decrease of neuropathic pain following local or systemic application of a local anesthetic is related to decrease of ectopic ongoing activity in injured afferent nerve fibers.