Mechanism of GABA involvement in post-traumatic trigeminal neuropathic pain: activation of neuronal circuitry composed of PKCγ interneurons and pERK1/2 expressing neurons.

Abstract

GABA disinhibition within the spinal dorsal horn has been implicated in pain hypersensitivity on injury in different neuropathic models. However, GABA alteration has been explored in only one study on trigeminal neuropathic pain. The present study investigated the implication of GABA in trigeminal dynamic mechanical allodynia (DMA) obtained after chronic constriction of the infraorbital nerve (CCI-IoN), and explored the cellular and molecular mechanisms by which GABA dysfunction induced DMA. Our data demonstrated a significant decrease in labelling in two GABA cell markers, glutamate acid decarboxylase (GAD67), and parvalbumin, in the medullary dorsal horn (MDH) of allodynic rats in comparison to sham rats. Increasing GABA by intracisternal injections of vigabatrin (VGB), a blocker of the catabolic enzyme GABA transaminase, alleviated pain behaviour and restored normal GABA cell marker expression in allodynic MDH. Interestingly, intracisternal VGB administration also significantly decreased PKCγ staining, i.e., of its phosphorylated active form and the number of pERK1/2 positive cells within the MDH. These two markers were highly expressed in allodynic MDH. The circuitry composed of PKCγ and pERK1/2 cells is silent under physiological conditions but is activated after CCI-IoN, therefore, switching touch stimuli to pain sensation. The decrease of GABA transmission constituted a key factor in the activation of this neuronal circuitry, which opens the gate for non-noxious stimuli to reach nociceptive projection neurons in lamina I.