The Known Biology of Neuropathic Pain and Its Relevance to Pain Management

Abstract

Patients with neuropathic pain are heterogeneous in pathophysiology, etiology, and clinical presentation. Signs and symptoms are determined by the nature of the injury and factors such as genetics, sex, prior injury, age, culture, and environment. Basic science has provided general information about pain etiology by studying the consequences of peripheral injury in rodent models. This is associated with the release of inflammatory cytokines, chemokines, and growth factors that sensitize sensory nerve endings, alter gene expression, promote post-translational modification of proteins, and alter ion channel function. This leads to spontaneous activity in primary afferent neurons that is crucial for the onset and persistence of pain and the release of secondary mediators such as colony-stimulating factor 1 from primary afferent terminals. These promote the release of tertiary mediators such as brain-derived neurotrophic factor and interleukin-1β from microglia and astrocytes. Tertiary mediators facilitate the transmission of nociceptive information at the spinal, thalamic, and cortical levels. For the most part, these findings have failed to identify new therapeutic approaches. More recent basic science has better mirrored the clinical situation by addressing the pathophysiology associated with specific types of injury, refinement of methodology, and attention to various contributory factors such as sex. Improved quantification of sensory profiles in each patient and their distribution into defined clusters may improve translation between basic science and clinical practice. If such quantification can be traced back to cellular and molecular aspects of pathophysiology, this may lead to personalized medicine approaches that dictate a rational therapeutic approach for each individual.

Spatial, transcriptomic and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition

“…This latter finding could be due to the innervation of upper cervical regions of the spinal cord by cranial muscles and dura or because of functional and anatomical similarities between spinal and medullary dorsal horns. Nevertheless, differences in the neuron subtypes that show strong associations for each type of pain reported is consistent with studies showing that chronic pain mechanisms and circuits differ by the nature of the injury 34,68,69 . It also fits that the number of neuron subtypes we identified as being highly enriched in open chromatin SNPs from patients with head/neck and multisite pain, which are likely to be combinations of inflammatory and neuropathic etiologies, was much greater than for the other types of pain.…”

Neuropathic pain; what we know and what we should do about it

“…The overall response of neuronal tissue to inflammatory mediators is described as “neuroinflammation” ( 167 – 170 ). It is characterized by glial cell proliferation and modulation of their phenotype as well as increased neuronal activity.…”

EZH2 Methyltransferase Regulates Neuroinflammation and Neuropathic Pain

“…At the pre-synaptic level, IL-1β enhances glutamatergic synaptic activities at the first synapses between the primary nociceptive afferents and dorsal horn neurons in the spinal dorsal horn by promoting glutamate release from presynaptic terminals 2 . IL-1β facilitates presynaptic glutamate release by enhancing presynaptic NMDA receptor activity [ 2 , 102 ]. At the postsynaptic level, IL-1β augments post-synaptic AMPA and NMDA receptor activities [ 4 , 62 , 103 ].…”

“…The development of novel analgesics with higher potency and safer features is an unmet need. Studies over the past three decades have shown that, under neuropathic conditions, pathologic glial cells play a critical role in aberrant neuronal activity in both the peripheral nerve and the spinal dorsal horn, termed peripheral and spinal central sensitizations, respectively [ 2 ]. Glial cells orchestrate neuronal activities in the peripheral and central nervous systems by releasing proinflammatory mediators (cytokines, chemokines, and others) [ 2 , 3 , 4 ].…”

“…Studies over the past three decades have shown that, under neuropathic conditions, pathologic glial cells play a critical role in aberrant neuronal activity in both the peripheral nerve and the spinal dorsal horn, termed peripheral and spinal central sensitizations, respectively [ 2 ]. Glial cells orchestrate neuronal activities in the peripheral and central nervous systems by releasing proinflammatory mediators (cytokines, chemokines, and others) [ 2 , 3 , 4 ]. In addition, glial cells in the CNS also control neuronal synaptic activities by clearing neurotransmitters via glial transporters [ 5 , 6 ].…”