Neuropathic pain: a maladaptive response of the nervous system to damage

Abstract

Neuropathic pain is triggered by lesions to the somatosensory nervous system that alter its structure and function so that pain occurs spontaneously and responses to noxious and innocuous stimuli are pathologically amplified. The pain is an expression of maladaptive plasticity within the nociceptive system, a series of changes that constitute a neural disease state. Multiple alterations distributed widely across the nervous system contribute to complex pain phenotypes. These alterations include ectopic generation of action potentials, facilitation and disinhibition of synaptic transmission, loss of synaptic connectivity and formation of new synaptic circuits, and neuroimmune interactions. Although neural lesions are necessary, they are not sufficient to generate neuropathic pain; genetic polymorphisms, gender, and age all influence the risk of developing persistent pain. Treatment needs to move from merely suppressing symptoms to a disease-modifying strategy aimed at both preventing maladaptive plasticity and reducing intrinsic risk.

Figure 1

Pain syndromes. A summary of key features that distinguish and characterize the four major pain syndromes; nociceptive pain (a), inflammatory pain (b), dysfunctional pain (c), and neuropathic pain (d). (Image adapted from Griffin & Woolf 2007)

Figure 1

Pain syndromes. A summary of key features that distinguish and characterize the four major pain syndromes; nociceptive pain (a), inflammatory pain (b), dysfunctional pain (c), and neuropathic pain (d). (Image adapted from Griffin & Woolf 2007)

Figure 2

Stimulus-response relations and pain mechanisms. A representation of the relationship between external noxious and innocuous stimuli and the sensory responses they evoke, depending on which afferent fiber is activated (nociceptor or low-threshold neuron) and whether the sensitivity of either the peripheral nervous system (PNS) or the central nervous system (CNS) is disturbed to amplify the response to stimuli (sensitization) and generate ectopic impulses.

Figure 3

A summary of the major mechanisms underlying peripheral neuropathic pain, their location, and the triggers responsible for their activation. (Image adapted from Griffin & Woolf 2007)

Figure 4

Phenotypic classification of pain. (a) Environmental and genetic factors determine the recruitment of adaptive and maladaptive neurobiological mechanisms. Patients will, depending on the mechanisms active, exhibit distinct constellations of symptoms and signs that constitute their pain phenotype. (b) When symptoms and signs are evaluated with standardized assessment tools, the phenotype of an individual patient can be compared with pain subtypes established in clinical trials. Correlation of treatment response with a matching pain subtype will then allow targeted analgesic therapy.

Figure 5

A summary of the major mechanisms connecting tetrahydrobiopterin (BH4) functions as a cofactor and its role in chronic pain.