Are Spinal GABAergic Elements Related to the Manifestation of Neuropathic Pain in Rat?

Abstract

Impairment in spinal inhibition caused by quantitative alteration of GABAergic elements following peripheral nerve injury has been postulated to mediate neuropathic pain. In the present study, we tested whether neuropathic pain could be induced or reversed by pharmacologically modulating spinal GABAergic activity, and whether quantitative alteration of spinal GABAergic elements after peripheral nerve injury was related to the impairment of GABAergic inhibition or neuropathic pain. To these aims, we first analyzed the pain behaviors following the spinal administration of GABA antagonists (1 μg bicuculline/rat and 5 μg phaclofen/rat), agonists (1 μg muscimol/rat and 0.5 μg baclofen/rat) or GABA transporter (GAT) inhibitors (20 μg NNC-711/rat and 1 μg SNAP-5114/rat) into naïve or neuropathic animals. Then, using W estern blotting, PCR or immunohistochemistry, we compared the quantities of spinal GABA, its synthesizing enzymes (GAD65, 67) and its receptors (GABAA and GABAB) and transporters (GAT-1, and -3) between two groups of rats with different severity of neuropathic pain following partial injury of tail-innervating nerves; the allodynic and non-allodynic groups. Intrathecal administration of GABA antagonists markedly lowered tail-withdrawal threshold in naïve animals, and GABA agonists or GAT inhibitors significantly attenuated neuropathic pain in nerve-injured animals. However, any quantitative changes in spinal GABAergic elements were not observed in both the allodynic and non-allodynic groups. These results suggest that although the impairment in spinal GABAergic inhibition may play a role in mediation of neuropathic pain, it is not accomplished by the quantitative change in spinal elements for GABAergic inhibition and therefore these elements are not related to the generation of neuropathic pain following peripheral nerve injury.

Spinal GABAergic Mechanisms in the Effects of Spinal Cord Stimulation in a Rodent Model of Neuropathic Pain: Is GABA Synthesis Involved?

“…In the literature, there are somewhat conflicting data on the relationship between changes in spinal GABAergic functions, GAD expression, and signs of neuropathy. It has recently been demonstrated that there was no relationship between the presence or absence of hypersensitivity and quantitative changes in spinal “GABAergic elements,” including GAD 65 and GAD 67, in spite of attenuating effects by intrathecal administration of GABA agonists . These findings are in accordance with some other studies that have failed to present evidence for an increased GABAergic cell apoptosis, changes in GABA bouton density, and in vesicular GABA transporters after nerve injury .…”

GABA, but not opioids, mediates the anti-hyperalgesic effects of 5-HT7 receptor activation in rats suffering from neuropathic pain

“…such that GABAergic inputs can become excitatory (De Koninck, 2007), enhancing GABAergic neurotransmission at spinal level has regularly been found to exert antinociceptive effects in neuropathic pain models (Braz et al, 2012;Lee et al, 2010), notably through activation of specific GABA A R containing the a2 and/or a3 subunits (Knabl et al, 2008;Munro et al, 2009). Direct electrophysiological recordings of dorsal horn neurons coupled to pharmacological and/or gene knock-in interventions specifically at a2 and/or a3 subunits-containing GABA A R would be of special interest to assess whether GABA A R-mediated anti-hyperalgesic effects of 5-HT 7 R activation involve these receptor subtypes.…”

Standardized fruit extract of Momordica charantia L protect against vincristine induced neuropathic pain in rats by modulating GABAergic action, antimitotoxic, NOS inhibition, anti-inflammatory and antioxidative activity

“…These observations indicated that the standardized MC has potential to interact with the GABA A & GABA B receptors and support the involvement of GABAergic system. Reduction in the levels of GABA and GABA receptors is well documented in different animal models of neuropathic pain (Eaton et al, 1998) and GABA agonists such as muscimol and baclofen showed beneficial effects on neuropathic pain (Lee et al, 2010).…”