Restoring the Spinal Pain Gate

Abstract

GABA_A receptors (GABA_ARs) and glycine receptors are key elements of the spinal control of nociception and pain. Compromised functioning of these two transmitter systems contributes to chronic pain states. Restoring their proper function through positive allosteric modulators should constitute a rational approach to the treatment of chronic pain syndromes involving diminished inhibitory spinal pain control. Although classical benzodiazepines (i.e., full agonists at the benzodiazepine binding site of GABA_ARs) potentiate synaptic inhibition in spinal pain controlling circuits, they lack clinically relevant analgesic activity in humans. Recent data obtained from experiments in GABA_AR point-mutated mice suggests dose-limiting sedative effects of classical nonspecific benzodiazepines as the underlying cause. Experiments in genetically engineered mice resistant to the sedative effects of classical benzodiazepines and studies with novel less sedating benzodiazepines have indeed shown that profound antihyperalgesia can be obtained at least in preclinical pain models. Present evidence suggests that compounds with high intrinsic activity at α2-GABA_AR and minimal agonistic activity at α1-GABA_AR should possess relevant antihyperalgesic activity without causing unwanted sedation. On-going preclinical studies in genetically engineered mice and clinical trials with more selective benzodiazepine site agonists should soon provide additional insights into this emerging topic.

Introduction

Chronic pain is a severe medical condition affecting millions of patients worldwide. It is almost generally accepted that neuronal and synaptic plasticity occurring at different levels of the neuraxis are major contributors to chronic pain (Luo et al., 2014, Sandkühler, 2009, Zeilhofer, Witschi and Johansson, 2009) (for a schematic illustration of the pain pathway, see Fig. 1). Some of these neuroplastic changes occur already in the peripheral terminals of nociceptors, which sense noxious stimuli arriving at the skin or in other peripheral tissues and convey them to the central nervous system. The central terminals of these nociceptors innervate the substantia gelatinosa (lamina II) of the spinal dorsal horn, or the trigeminal nucleus of the brainstem in case of those nociceptors coming from the facial skin or the meninges. From there, signals are propagated through various relay stations in the brainstem, midbrain, and thalamus to several cortical areas which give rise to the conscious sensation of pain. One site that has attracted particular attention in pain-related neuroplasticity is the spinal dorsal horn, which constitutes as the first site of synaptic integration in the pain pathway. Neurons located in the spinal dorsal horn integrate primary afferent sensory signals of painful and non-painful modalities with input from descending fiber tracts, which can either inhibit or facilitate pain. Inhibitory interneurons have been attributed a critical role in this process already in the gate-control-theory of pain (Fig. 2; Melzack & Wall, 1965). Although some of the synaptic connections proposed in the original scheme do apparently not exist, plenty of evidence indicates that compromising the function of inhibitory dorsal horn neurons induces symptoms reminiscent of chronic pain syndromes in humans. Animals develop an exaggerated sensitivity to painful stimuli (hyperalgesia), they respond with withdrawal responses upon exposure to stimuli, which are normally not felt as painful (allodynia), and they also show signs of spontaneous discomfort. Many lines of evidence indicate that typical causes of chronic pain such as inflammation or neuropathies compromise the function of inhibitory interneurons in the spinal dorsal horn through different mechanisms (for a review, see Zeilhofer, Benke, & Yévenes, 2012). According to this concept, a facilitation of inhibitory neurotransmission should be a rational strategy for the treatment of many chronic pain states. Yet, none of the established analgesics act- through a facilitation of inhibitory neurotransmission. In the following text, we will review mechanisms of pain-related spinal disinhibition and evidence supporting the concept that novel subtype-selective benzodiazepine agonists would be suitable for the treatment of chronic pain syndromes. In the context of this review, we use the term “benzodiazepine” for all agonists at the benzodiazepine binding site of γ-aminobutyric acid type A receptors (GABA_ARs) independent of their chemical structure. It should also be mentioned here that GABA_ARs exist, which are resistant to modulation by classical benzodiazepines. These receptors contain α4 or α6 subunits instead of α1, α2, α3, or α5, or a γ1 or δ subunit instead of the γ2 subunit. These benzodiazepine-insensitive receptors are quite abundant in several brain regions (e.g., thalamus and cerebellum), but their expression in the spinal cord is sparse.