Chronic Pain States: Pharmacological Strategies to Restore Diminished Inhibitory Spinal Pain Control

Abstract

Potentially noxious stimuli are sensed by specialized nerve cells named nociceptors, which convey nociceptive signals from peripheral tissues to the central nervous system. The spinal dorsal horn and the trigeminal nucleus serve as first relay stations for incoming nociceptive signals. At these sites, nociceptor terminals contact a local neuronal network consisting of excitatory and inhibitory interneurons as well as of projection neurons. Blockade of neuronal inhibition in this network causes an increased sensitivity to noxious stimuli (hyperalgesia), painful sensations occurring after activation of non-nociceptive fibers (allodynia), and spontaneous pain felt in the absence of any sensory stimulation. It thus mimics the major characteristics of chronic pain states. Diminished inhibitory pain control in the spinal dorsal horn occurs naturally, e.g., through changes in the function of inhibitory neurotransmitter receptors or through altered chloride homeo-stasis in the course of inflammation or nerve damage. This review summarizes our current knowledge about endogenous mechanisms leading to diminished spinal pain control and discusses possible ways that could restore proper inhibition through facilitation of fast inhibitory neurotransmission.

Glycine transport inhibitors for the treatment of pain

“…Inhibitory glycinergic neurons and receptors are found throughout the CNS, but are most abundant in the dorsal horn of the spinal cord, particularly in lamina III [9][10][11]. GlyT1, GlyT2…”

“…These glycinergic neurons contribute to inhibition of nociceptive signalling and have important roles in segregating nociceptive and non-noxious information pathways [1,11] (see Figure 2). Dysfunctions of glycinergic systems, together with GABAergic systems [14][15][16][17][18][19], contribute to neuropathic and inflammatory pain.…”

“…This is due to a reduction in the activity of the potassium chloride co-transporter (KCC2) [27] that leads to an increase in intracellular chloride, so activation of GABA or glycine receptors causes depolarization and a pronociceptive excitation of these pain transmission neurons. However, GlyT inhibitors would not be expected to strongly exacerbate this pronociceptive adaptation because inhibitory neurotransmission in lamina I of the dorsal horn is predominantly GABAergic [28] and GlyT2 expression is relatively sparse in this region [9][10][11].…”

“…In interneurones of the spinal cord, both glycine and GABA can be present in the same synaptic vesicles, which is presumably due to the presence of both GlyT2 and a GABA transporter capable of maintaining the intracellular GABA concentration at similar levels as glycine [31,32]. However, segregation of GABAergic and glycinergic neurotransmission in dorsal spinal cord is extensive [11,19,28], with GABAergic synapses dominating in laminae I and IIo, and glycinergic transmission dominating in laminae Iii and III. This selectivity is presumably generated by cell type selective expression of GlyT2, GABA transporters and subsynaptic receptor types [11].…”

“…However, segregation of GABAergic and glycinergic neurotransmission in dorsal spinal cord is extensive [11,19,28], with GABAergic synapses dominating in laminae I and IIo, and glycinergic transmission dominating in laminae Iii and III. This selectivity is presumably generated by cell type selective expression of GlyT2, GABA transporters and subsynaptic receptor types [11]. In the spinal cord, GlyT1 is expressed by astrocytes and neurons [6][7][8] and serves different purposes at inhibitory and excitatory synapses ( Figure 1).…”