Morphine-induced depression of spinal excitation is not altered following acute disruption of GABA(A) or GABA(B) receptor activity.
Loss of spinal inhibitory mechanisms is thought to contribute to the pathophysiology of abnormal pain states, including neuropathic pain. By using an evoked spinal field potential technique, the hypothesis was tested here that decreased spinal GABAergic control underlies poor response to morphine (MOR) that often accompanies neuropathic pain. Therefore, field potentials evoked by electrical peripheral nerve stimulation during spinal superfusion with MOR were recorded in rats rendered neuropathic by a spinal nerve ligation (SNL) procedure, and compared to responses recorded in naïve rats. MOR effects on evoked field potentials were then assessed in rats in which spinal GABAergic inhibition had been acutely reduced by treatment with GABA(A) and GABA(B) receptor-antagonists. In naïve animals, field potentials evoked by peripheral C fibre-input were significantly decreased by spinal superfusion with 1 microM MOR, whereas those elicited by Adelta fibre input were reduced to a lesser extent also (10 microM, p < 0.05). Nine to eleven days after surgery,animals subjected to SNL exhibited significantly reduced thresholds to plantar stimulation with von Frey filaments. In electrophysiological experiments, a small but significant decrease of the IC50 value (2.17 +/- 0.38 microM) for MOR was found in rats subjected to SNL, relative to naïve rats (8.65 +/- 0.76 microM). In contrast, MOR failed to reduce field potentials evoked by peripheral Adelta fibre-activation at any dose tested (up to 1 mM). C fibre- and Adelta fibre-evoked spinal field potentials disinhibited by prior application of the GABA(B) or GABA(A) receptor-antagonists CGP35348 (1 mM) or bicuculline (50 microM), respectively, were both significantly reduced by MOR, with IC50 values not significantly differing from those in naïve animals. Two-way analysis of variance revealed no interaction of MOR with either CGP354348 (p = 0.42) or BIC (p = 0.14). Evidence is presented here that injury to the primary afferent system results in significant changes in the ability of spinal MOR to depress field potentials evoked by peripheral input. However, the present findings do not support a pathogenic role for decreased GABAergic inhibition in such changes.
Buesa
Itsaso
I
Department of Neurosciences, School of Medicine and Dentistry, Basque Country University, Barrio Sarriena s/n, 48940 Leioa, Spain.
Urrutia
Andrés
A
Bilbao
Juan
J
Aguilera
Luciano
L
Zimmermann
Manfred
M
Azkue
Jon Jatsu
JJ
D000208:Acute Disease; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology; D008026:Ligation; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D018080:Receptors, GABA-B / Q000502:physiology*; D013127:Spinal Nerves / Q000187:drug effects / Q000502:physiology
D000701:Analgesics, Opioid; D018756:GABA Antagonists; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D009020:Morphine