Peripheral GABAA receptors: evidence for peripheral primary afferent depolarization

SM Carlton, S Zhou, RE Coggeshall - Neuroscience, 1999 - Elsevier
SM Carlton, S Zhou, RE Coggeshall
Neuroscience, 1999Elsevier
We propose that the primary afferent depolarization that follows GABAA receptor activation
in the spinal cord also occurs in the periphery. As evidence, the present study localizes
β2/β3 and α1 subunits of the GABAA receptor on 10–14% of the unmyelinated primary
afferents axons in the glabrous skin of the cat paw. Behavioral studies demonstrate that local
peripheral injection of the GABAA agonist muscimol at a low concentration (2.0 μM)
attenuates, and at a high concentration (1mM) enhances, formalin-induced nociceptive …
We propose that the primary afferent depolarization that follows GABAA receptor activation in the spinal cord also occurs in the periphery. As evidence, the present study localizes β2/β3 and α1 subunits of the GABAA receptor on 10–14% of the unmyelinated primary afferents axons in the glabrous skin of the cat paw. Behavioral studies demonstrate that local peripheral injection of the GABAA agonist muscimol at a low concentration (2.0μM) attenuates, and at a high concentration (1mM) enhances, formalin-induced nociceptive behaviors. Intraplantar injection of muscimol alone at a high dose evokes thermal hyperalgesia. Bicuculline, a GABAA antagonist, prevents these muscimol-induced changes in behavior. The muscimol-induced effects are due to local rather than systemic or central activation of GABAA receptors, as such effects are not observed in the contralateral paw. We interpret these findings to indicate that activation of GABAA receptors by low concentrations of muscimol depolarizes peripheral primary afferent terminals, a phenomenon we call peripheral primary afferent depolarization, in turn reducing the size of the peripheral action potentials and concomitantly reducing the amount of algogenic substances released from the peripheral terminals of these fibers. This sequence of events presumably results in a reduction in nociceptor activation. Higher concentrations of muscimol further depolarize GABAA receptor-containing terminals, which then initiates action potentials in nociceptors analogous to the appearance of dorsal root reflexes that arise following activation of GABAA receptors on central primary afferent terminals. These latter events reverse the analgesic effects of GABAA ligands and lead to potentiation of nociceptive input. Thus, the present study provides anatomical and behavioral evidence supporting a bimodal role for GABAA receptors in the modulation of peripheral nociceptive transmission.
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