Neuropathic Pain-Signaling in Dorsal Horn Neurons
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Neuropathic Pain-Signaling in Dorsal Horn Neurons

Living organisms need to sense noxious stimuli in their immediate environment to avoid potentially hazardous situations and thus survive. To this end, multicellular creatures have evolved a specialized apparatus: the Nociceptors to differentiate innocuous from noxious stimuli. Multiple transduction molecules within the Nociceptor enable the organisms for sensing heat, cold; for perceiving noxious mechanical sensations; and, for detecting noxious chemicals. Activation of sufficient numbers of such transducing molecules in peripheral Nociceptors in skin and muscle or in visceral organs initiates action potentials, which are conducted through thin unmyelinated C fibers and myelinated A-Delta fibers to the CNS (Central Nervous System). The signal is first conducted to second-order sensory Neuron in the spinal dorsal horn, and then through supraspinal pathways to the cerebral cortex, eliciting the sensation of pain. The perception of pain (called Nociception) depends on specifically dedicated receptors and pathways. Pain sensation can be a manifestation of peripheral sensitization [increased excitability of Nociceptors (primary Nociceptive Neuron) at the distal nerve terminal, at the axon, or at the cell body] or central sensitization involving activity-dependent plasticity of Nociceptive Neuron in the CNS, particularly in the Dorsal Horn of the Spinal Cord (Ref.1 & 2).

Increased long-lasting discharge of peripheral Nociceptors modifies neuronal phenotype and function in the CNS. These plastic changes in the spinal cord and in the brain, leading to increased responsiveness, are referred to as central sensitization. Central sensitization plays a major role in the heightened pain that often follows nerve injury. Although Nociceptive pain (physiological pain) requires intense, high-threshold stimulation and is typically transient, pathological pain (clinical pain) associated with inflammation of peripheral tissue that arises from the initial damage or from lesions to the Nervous System (Neuropathic Pain) is often persistent. Damage to the nervous system can cause Neuropathic Pain. Neuropathic Pain can arise from an "injury discharge" originating at the site of nerve injury, as well as from the development of ectopic impulses (increased spontaneous activity) in the injured nerve. Many patients suffer from Neuropathic Pain due to injury to the PNS (Peripheral Nervous System) [including peripheral nerves, DRG (Dorsal Root Ganglia), and dorsal roots] or the CNS (Spinal Cord and Thalamus). These injuries may result from surgery, diabetic neuropathy, amputation, viral infection, trauma, stroke, and so forth (Ref.2 & 3). Multiple inflammatory mediators released from damaged tissue not only acutely excite primary sensory Neuron in the peripheral nervous system, producing ectopic discharge, but also lead to a sustained increase in their excitability. Hyperexcitability develops in the CNS Dorsal Horn Neuron, and both peripheral and spinal elements contribute to Neuropathic Pain, so that spontaneous pain may occur or normally innocuous stimuli may produce pain. Inflammatory mediators and aberrant neuronal activity activate several signaling pathways [including PKA (Protein Kinases-A), PKC (Protein Kinase-C), CalmKs (Calcium/Calmodulin-Dependent Protein Kinases), and MAPKs (Mitogen-Activated Protein Kinases)] in Postsynaptic Dorsal Horn Neuron that mediate the induction and maintenance of Neuropathic pain through both post-translational and transcriptional mechanisms (Ref.1 & 3).

Peripheral nerve injury induces release of the Neurotransmitter Glutamate and the Neuromodulators: Tac1 (Tachykinin-1) and BDNF (Brain Derived Neurotrophic Factor) from the central terminals of Primary Afferents. Glutamate is the major excitatory neurotransmitter in the Spinal Cord and it acts on ionotropic AMPA (Glutamate Receptor, Ionotropic, AMPA), and NMDARs (N-Methyl D-Aspartate Receptors) as well as on MGLURs (Gutamate Receptor, Metabotropic) (Ref.4 & 5). Whereas AMPA receptors are important for the rapid excitatory synaptic transmission of physiological nociception, NMDARs play a critical role in plasticity in the CNS. Activation of NMDARs and Ca2+ permeable AMPA receptors in the spinal cord leads to Ca2+ influx. Stimulation of MGLURs and NK1R activates IP3 (Inositol Triphosphate), through PLC (Phospholipase-C), and stimulates Ca2+ release from intracellular stores. The increase in intracellular Ca2+ activates CalmKs and PKC (Ref.2 & 3). BDNF released from Presynaptic Terminals also acts on postsynaptic TRKB (Tyrosine Kinase Receptor-B) receptors in the Dorsal Horn, which increases the activity of NMDARs through tyrosine phosphorylation of Src; thus, contributing to the induction of Neuropathic pain. PKC, CalmK and Src all increase the activity of NMDARs (Ref.6). Activation of ERKs (Extracellular Signal-Regulated Kinases) by TRKB, PKA, PKC and PI3K (Phosphatidylinositde-3 Kinase), an activation that involves NMDARs, AMPA receptors, and MGLURs can suppress the activity of potassium channel Kv4.2/KCND2 (Potassium Voltage-Gated Channel, Shal-Related Subfamily, Member-2), which generally suppresses excitability of the Neuron. CalmKs positively regulate the activity of NMDARs, and AMPA receptors. These post-translational steps result in an overall increased sensitivity of Dorsal Horn Neuron to afferent input, contributing to the generation of central sensitization. The activation of ERKs, PKA, and CalmKs activates the transcription factors CREB (cAMP Response Element-Binding Protein), Elk1, and c-Fos, leading to increased transcription of Prodynorphin, Tac1, nNOS (Neuronal Nitric Oxide Synthase) COX2 (Cyclooxygenase-2), SCn (Na+ Channel), and Alpha2Delta-CaCn (Ca2+ Channel) subunit, TRKB etc. The protein or peptide products of these genes act together to maintain heightened excitability and synaptic responsiveness, and thus support central sensitization and cause Neuropathic Pain (Ref.2, 3 & 5).

The most distinctive symptom of Neuropathic pain is Mechanical Allodynia (painful responses to normally innocuous tactile stimuli), although Neuropathic pain is also often characterized by Hyperalgesia (increased responsiveness to noxious stimuli) to mechanical and thermal stimuli. In addition to stimulus-evoked pain, many patients have spontaneous pain, described as shooting, lancinating, or burning pain. Currently available drugs provide relief of Neuropathic pain in only a fraction of such patients, sometimes of enduring quality but often lasting no longer than the drug’s presence at the site. ERK activation in Dorsal Horn Neuron is Nociceptive-specific and can be suppressed by several Analgesics, and therefore, inhibition of ERKs has the potential of alleviating Neuropathic pain. Development of specific inhibitors for ERKs may lead to new therapies for Neuropathic pain (Ref.4 & 7).