Pre- and postsynaptic inhibitory control in the spinal cord dorsal horn

Abstract

Sensory information transmitted to the spinal cord dorsal horn is modulated by a complex network of excitatory and inhibitory interneurons. The two main inhibitory transmitters, GABA and glycine, control the flow of sensory information mainly by regulating the excitability of dorsal horn neurons. A presynaptic action of GABA has also been proposed as an important modulatory mechanism of transmitter release from sensory primary afferent terminals. By inhibiting the release of glutamate from primary afferent terminals, activation of presynaptic GABA receptors could play an important role in nociceptive and tactile sensory coding, while changes in their expression or function could be involved in pathological pain conditions, such as allodynia.

Figure 1.

Blockade of GABA_A and glycine receptors with bicuculline and strychnine enhances excitability of inhibitory neurons in mouse dorsal horn. Shown are examples of action potentials induced by current injection under three conditions: (1) control; NBQX [10 μM] and AP5 [50 μM]; (2) BIC; NBQX, AP5, and bicuculline [10 μM]; and (3) BIC+STR; NBQX, AP5, bicuculline, and strychnine [1 μM]. Resting membrane potential was kept at −65 mV. Left panel shows responses to a small current injection in the three conditions, and the right panel shows responses to a larger current injection. Bottom traces show injected currents. Taken with permission from Ref. .

Figure 2.

GAD67-eGFP⁺ neurons have regionally distinct properties of synaptic inhibitory input. Part A shows soma locations of glycine-dominant (Gly-d, gray circles) and GABA-dominant (GABA-d, black circles) neurons recorded from post-natal day 29–32 (5W) mice. Right and upper sides of the schematic diagram show lateral and dorsal edges of the dorsal horn, respectively. Laminae I, II, and III are separated by dotted lines. (B) Gly-d neurons are the major population at the lamina II/III border (n = 12), while GABA-d neurons (black bars) are the major population in lamina I and IIo (n = 11). Bars indicate the incidence of neurons located in laminae I/IIo, and at the laminae II/III border. Taken with permission from Ref. .

Figure 3.

Schematic representation of a proposed polysynaptic excitatory pathway connecting lamina III to lamina I projection neurons. This pathway is normally under powerful inhibitory control mediated by GABA and glycine released from inhibitory neurons. Presynaptic inhibition mediated by GABA_A or GABA_B receptors in the spinal cord dorsal horn is illustrated in detail for the Aβ fiber synaptic terminal onto a lamina III neuron, but also occurs on nociceptor PAF terminals. Stimulation of cutaneous tactile fibers induces GABA release from inhibitory interneurons, causing the activation of GABA_A or GABA_B receptors expressed on primary afferent terminals and the inhibition of glutamate release onto lamina III–IV neurons.