GABA decreases in the spinal cord dorsal horn after peripheral neurectomy

Castro-Lopes, José Manuel; Tavares, Isaura; Coimbra, Antonio

doi:10.1016/0006-8993(93)90167-l

Cited by 252 publications

(139 citation statements)

References 45 publications

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“…3 and 4). This adds further support to a report on the antinociceptive effect of baclofen on evoked symptoms (mechanical allodynia) in neuropathic animals 5 and on a rat model of trigeminal neuropathic pain 17. However, Castro-Lopes et al 18 reported on a significant fall in the number of GABA-immunoreactive cells in laminae I-III of the rat spinal cord, after sciatic nerve transection. In Bennet's model, however, only a partial lesion is present, and besides the possible partial depletion of GABA B receptor induced by the lesion, if any, a compensating up-regulation may hypothetically occur.…”

Section: Discussionmentioning

confidence: 98%

The effect of baclofen on spontaneous and evoked behavioural expression of experimental neuropathic chronic pain

Santos

Castro-Costa

Giffoni

et al. 1999

Arq. Neuro-Psiquiatr.

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-Baclofen (β-p-chlorophenyl-GABA) has been used in humans to treat spasticity, as well as trigeminal neuralgia. Since GABA (gamma-aminobutyric acid) has been implicated in inhibitory and analgesic effects in the nervous system, it was of interest to study the effect of baclofen in experimental neuropathic pain. With this purpose, experiments were carried out in 17 neuropathic rats with constrictive sciatic injury, as described by Bennet and Xie (1988), taking as pain parameters scratching behaviour and the latency to the thermal nociceptive stimulus. The results showed that baclofen induces, in a dose-dependent manner, significant decrease (p < 0.05) of scratching behaviour and significant increase (p < 0.05) of the latency to the nociceptive thermal stimulus. The absence of antagonism of naloxone suggested a non-participation of an opioid-mediated mechanism in this analgesic effect of baclofen on experimental neuropathic pain.KEY WORDS: baclofen, experimental neuropathic pain, Bennet's model, scratching behaviour, thermal stimulus, analgesia.Efeito do baclofeno sobre a expressão comportamental espontânea e evocada da dor crônica neuropática experimental RESUMO -O baclofeno (β-p-clorofenil-GABA) é usado em seres humanos para tratar espasticidade, assim como neuralgia do trigêmeo. Como o GABA (ácido amino-gama-butírico) tem sido implicado em efeitos inibitórios e analgésicos no sistema nervoso, tornou-se de interesse estudar o efeito do baclofeno em dor neuropática experimental. Com esse objetivo, foram realizados experimentos em 17 ratos neuropáticos com lesão constritiva do nervo ciático, como descrito por Bennet e Xie (1988), tomando como parâmetros de dor o comportamento de coçar-se (scratching) e a latência ao estímulo térmico nociceptivo. Os resultados mostraram que o baclofeno induziu, de forma dose-dependente, diminuição significativa (p < 0,05) do comportamento de coçar-se e aumento significativo (p < 0,05) da latência ao estímulo térmico nociceptivo. A ausência de antagonismo pela naloxona sugere a não participação de mecanismo opióide-mediado nesse efeito analgésico do baclofeno em dor neuropática experimental.PALAVRAS-CHAVE: baclofeno, dor neuropática experimental, modelo de Bennet, comportamento de coçar-se (scratching), estímulos térmicos, analgesia.The study of neuropathic pain remains a serious challenge, since its underlying mechanisms have not yet been elucidated and consequently there is currently a lack of effective treatment. Among the different attempts to alleviate this kind of chronic pain in humans, baclofen (β-p-chlorophenyl-

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Section: Discussionmentioning

confidence: 98%

The effect of baclofen on spontaneous and evoked behavioural expression of experimental neuropathic chronic pain

Santos

Castro-Costa

Giffoni

et al. 1999

Arq. Neuro-Psiquiatr.

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“…In addition, the reduction in the amplitude of glycinergic IPSCs seemed to be greater than that of GABAergic IPSCs in the spinal cord of nerve-injured rats. Some studies reported that the number of GABA-immunoreactive neurons in the spinal dorsal horn is reduced after nerve injury (Castro-Lopes et al, 1993;Ibuki et al, 1997;Moore et al, 2002). However, other studies have shown that nerve injury does not cause any significant loss of GABAergic and glycinergic neurons in the spinal dorsal horn (Polgá r et al, 2003(Polgá r et al, , 2005Hermanns et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Functional Plasticity of Group II Metabotropic Glutamate Receptors in Regulating Spinal Excitatory and Inhibitory Synaptic Input in Neuropathic Pain

Zhou

Chen²,

Chen

et al. 2010

J Pharmacol Exp Ther

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Metabotropic glutamate receptors (mGluRs) are involved in the modulation of synaptic transmission and plasticity. Group II mGluRs in the spinal cord regulate glutamatergic input, but their functional changes in neuropathic pain are not clear. In this study, we determined the plasticity of spinal group II mGluRs in controlling excitatory and inhibitory synaptic transmission and nociception in neuropathic pain. Neuropathic pain was induced by spinal nerve ligation in rats, and whole-cell voltage-clamp recordings of glutamatergic excitatory postsynaptic currents (EPSCs) and spontaneous and miniature GABAergic and glycinergic inhibitory postsynaptic currents (sIPSCs and mIPSCs, respectively) were performed in spinal cord slices. The specific group II mGluR agonist (2S,2ЈR,3ЈR)-2-(2Ј,3Ј-dicarboxycyclopropyl)glycine (DCG-IV) had a similar inhibitory effect on monosynaptic EPSCs evoked from the dorsal root in sham and nerve-injured rats. However, DCG-IV produced a greater inhibitory effect on evoked polysynaptic EPSCs and the frequency of spontaneous EPSCs in nerveinjured rats than in control rats. Although DCG-IV similarly reduced the frequency of GABAergic sIPSCs and mIPSCs in both groups, it distinctly inhibited the frequency of glycinergic sIPSCs and mIPSCs only in nerve-injured rats. The DCG-IV effect was blocked by the group II mGluR antagonist but not by the N-methyl-D-aspartate receptor antagonist. Strikingly, intrathecal injection of DCG-IV dose-dependently attenuated allodynia and hyperalgesia in nerve-injured rats but produced hyperalgesia in control rats. Our study provides new information that nerve injury up-regulates group II mGluRs present on glutamatergic and glycinergic interneurons in the spinal cord. Activation of group II mGluRs reduces neuropathic pain probably by attenuating glutamatergic and glycinergic input to spinal dorsal horn neurons.

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“…Clinical studies have established that the symptom, called dynamic mechanical allodynia, is mediated by sensory A␤ fibers normally responsible for the detection of innocuous mechanical stimuli only (Campbell et al, 1988). It also involves alterations in central processing of sensory information by dorsal horn neurons (Woolf and Salter, 2006), including disinhibition through reduced inhibitory transmitter synthesis and/or release (Castro-Lopes et al, 1993;Wiesenfeld-Hallin et al, 1997), loss of inhibitory interneurons (Moore et al, 2002), block of inhibitory receptors (Ahmadi et al, 2002;Harvey et al, 2004), shift in anion gradient (Coull et al, 2005) or altered descending inhibitory modulation from the brain (Vanegas and Schaible, 2004). Glycine inhibitory dysfunction has successfully been used as a model of allodynia (Beyer et al, 1985;Yaksh, 1989;Sherman and Loomis, 1994).…”

Section: Introductionmentioning

confidence: 99%

Glycine Inhibitory Dysfunction Induces a Selectively Dynamic, Morphine-Resistant, and Neurokinin 1 Receptor- Independent Mechanical Allodynia

Miraucourt¹,

Moisset²,

Dallel³

et al. 2009

J. Neurosci.

118

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Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. We recently provided a novel perspective on the mechanisms of this symptom by showing that a simple switch in trigeminal glycine synaptic inhibition can turn touch into pain by unmasking innocuous input to superficial dorsal horn nociceptive specific neurons through a local excitatory, NMDA-dependent neural circuit involving neurons expressing the gamma isoform of protein kinase C. Here, we further investigated the clinical relevance and processing of glycine disinhibition. First, we showed that glycine disinhibition with strychnine selectively induced dynamic but not static mechanical allodynia. The induced allodynia was resistant to morphine. Second, morphine did not prevent the activation of the neural circuit underlying allodynia as shown by study of Fos expression and extracellularsignal regulated kinase phosphorylation in dorsal horn neurons. Third, in contrast to intradermal capsaicin injections, light, dynamic mechanical stimuli applied under disinhibition did not produce neurokinin 1 (NK1) receptor internalization in dorsal horn neurons. Finally, light, dynamic mechanical stimuli applied under disinhibition induced Fos expression only in neurons that did not express NK1 receptor. To summarize, the selectivity and morphine resistance of the glycine-disinhibition paradigm adequately reflect the clinical characteristics of dynamic mechanical allodynia. The present findings thus reveal the involvement of a selective dorsal horn circuit in dynamic mechanical allodynia, which operates through superficial lamina nociceptive-specific neurons that do not bear NK1 receptor and provide an explanation for the differences in the pharmacological sensitivity of neuropathic pain symptoms.

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GABA decreases in the spinal cord dorsal horn after peripheral neurectomy

Cited by 252 publications

References 45 publications

The effect of baclofen on spontaneous and evoked behavioural expression of experimental neuropathic chronic pain

The effect of baclofen on spontaneous and evoked behavioural expression of experimental neuropathic chronic pain

Functional Plasticity of Group II Metabotropic Glutamate Receptors in Regulating Spinal Excitatory and Inhibitory Synaptic Input in Neuropathic Pain

Glycine Inhibitory Dysfunction Induces a Selectively Dynamic, Morphine-Resistant, and Neurokinin 1 Receptor- Independent Mechanical Allodynia

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