Deconstructing the Neuropathic Pain Phenotype to Reveal Neural Mechanisms

Abstract

After nerve injury maladaptive changes can occur in injured sensory neurons and along the entire nociceptive pathway within the CNS, which may lead to spontaneous pain or pain hypersensitivity. The resulting neuropathic pain syndromes present as a complex combination of negative and positive symptoms, which vary enormously from individual to individual. This variation depends on a diversity of underlying pathophysiological changes resulting from the convergence of etiological, genotypic and environmental factors. The pain phenotype can serve therefore, as a window on underlying pathophysiological neural mechanisms, and as a guide for developing personalized pain medicine.

Glycine transport inhibitors for the treatment of pain

“…Acute, reversible, adaptive changes in the sensory nervous system also lead to sensory hypersensitivity that serves a protective function while the damaged tissue is healing. However, nerve injury in the peripheral or central nervous system (CNS) can lead to chronic pain that persists well beyond the period of tissue damage, lasting for more than 3-6 months and is characterized by spontaneous pain, hyperalgesia (an exaggerated response to noxious stimuli), and allodynia in thermal and mechanical modalities (the perception of normally innocuous stimuli such as mild cooling or light touch as painful) [1]. Although currently available analgesics effectively treat many acute nociceptive and inflammatory pain conditions, chronic pain symptoms are very difficult to manage.…”

“…Although currently available analgesics effectively treat many acute nociceptive and inflammatory pain conditions, chronic pain symptoms are very difficult to manage. A large body of evidence in animal models and humans suggest that chronic pain states involve persistent pathological adaptations in excitatory neurotransmission, neuron-glial interactions and inhibitory neurotransmission (reviewed by [1]). Drugs that can enhance inhibitory neurotransmission, such as inhibitors of the glycine transporters (GlyTs), reverse signs of chronic pain in animal models, strongly suggesting potential efficacy for managing chronic pain.…”

“…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.…”

“…Kato et al [23] used in vivo patch recording to demonstrate that partially overlapping, monosynaptic GABAergic and glycinergic pathways from RVM to lamina II inhibit mechanical nociceptive responses. There is strong evidence that these descending inhibitory mechanisms are suppressed in chronic pain states, which may contribute to various symptoms of chronic pain [1,20]. GlyT2 inhibitors could relieve many aspects of chronic pain by elevating synaptic glycine concentrations and thereby restoring glycinergic descending inhibition.…”

“…Low and high doses of ALX5407 provide analgesia, but medium doses exacerbate nociception, which may be related to elevations of glycine in both inhibitory and excitatory synapses. Activation of NMDA receptors might be expected to worsen pain symptoms because they are involved in spinal sensitization mechanisms in chronic pain states [1] and for these reasons further development of GlyT1 inhibitors for the treatment of pain may be limited.…”