Increased Nociceptive Input Rapidly Modulates Spinal GABAergic Transmission Through Endogenously Released Glutamate

Abstract

Stimulation of nociceptive primary afferents elicits pain by promoting glutamatergic transmission in the spinal cord. Little is known about how increased nociceptive input controls GABAergic tone in the spinal dorsal horn. In this study, we determined how increased nociceptive inflow affects GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of lamina II neurons by using whole cell recordings in rat spinal cord slices. Bath application of capsaicin for 3 min induced a long-lasting inhibition of sIPSCs in 50% of the neurons tested. In the other half of the neurons, capsaicin either increased the frequency of sIPSCs (34.6%) or had no effect on sIPSCs (15.4%). The GABA A current elicited by puff application of GABA was not altered by capsaicin. Capsaicin did not inhibit sIPSCs in rats treated with intrathecal pertussis toxin. Also, capsaicin failed to inhibit sIPSCs in the presence of ionotropic glutamate receptor antagonists or in the presence of both LY341495 and CPPG (group II and group III metabotropic glutamate receptor antagonists, respectively). However, when LY341495 or CPPG was used alone, capsaicin still decreased the frequency of sIPSCs in some neurons. Additionally, bradykinin significantly inhibited sIPSCs in a population of lamina II neurons and this inhibitory effect was also abolished by LY341495 and CPPG. Our study provides novel information that stimulation of nociceptive primary afferents rapidly suppresses GABAergic input to many dorsal horn neurons through endogenous glutamate and activation of presynaptic group II and group III metabotropic glutamate receptors. These findings extend our understanding of the microcircuitry of the spinal dorsal horn involved in nociception. I N T R O D U C T I O NNociceptive information generated from noxious stimuli is relayed primarily by unmyelinated primary afferents to secondorder neurons in the superficial dorsal horn of the spinal cord. The resulting pain intensity and duration often increase after the initial tissue or nerve damage. Tissue and peripheral nerve injury can sensitize primary afferents and spinal cord dorsal horn neurons, which results in secondary pain hypersensitivity (LaMotte et al. 1982; Torebjork et al. 1992; Woolf et al. 1988). The release of inflammatory mediators from injured tissues and inflammatory cells, including prostaglandins (Martin et al. 1987; Trebino et al. 2003) and bradykinin (Liang et al. 2001;Rueff and Dray 1993), can stimulate and sensitize nociceptors (peripheral sensitization). Furthermore, increased release of glutamate from primary afferents and activation of postsynaptic ionotropic glutamate receptors (iGluRs) in the spinal cord can enhance the excitability of dorsal horn neurons (central sensitization) (Dougherty et al. 1992;Leem et al. 1996). However, the cellular mechanisms for the hypersensitivity of dorsal horn neurons after tissue and nerve injury are not fully known.The lamina II of the spinal cord is a critical site for the relay and processing of dynamic modulation of sensory information. Ye...

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