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.

Copyright © 2012 Elsevier Inc. All rights reserved.

Figures

Figure 1. The nociceptive pain circuit

High threshold nociceptors are activated by intense mechanical, thermal or chemical stimuli and feed this information to nociceptive neurons in the spinal cord, which project via the thalamus to cortical areas generating the sensory and emotional qualities of pain. These spinal cord pathways are subject to descending inhibitory and facilitatory influences from the brainstem. Normally, activity in low threshold afferents is carried by independent peripheral and central pathways and only generates innocuous sensations.

Figure 2. From Etiology to Neuropathic Pain

The neuropathic syndrome is the end result of an initiating disease combined with individual contributing factors, such as genotype and environmental factors like diet and life style, all of which lead to individual combinations of pathophysiological mechanisms, manifesting as an individual neuropathic pain phenotype.

Figure 3. Peripheral Sensitization

Changes in the sensitivity of the peripheral terminals of nociceptors to stimuli can contribute to evoked pain. This can occur through inflammatory mediators sensitizing signal transducer proteins, persistent activation of transducer proteins by endogenous agonists, inherited polymorphisms of transducer proteins, or an increase in membrane excitability.

Figure 4. Central Sensitization

Changes in the spinal cord that lead to the strengthening of synaptic input from both nociceptor and low-threshold mechano-receptors onto nociceptive neurons contribute to an amplification of pain, with a reduction in its threshold, an expansion in its spatial extent, and a change in its temporal characteristics. The recruitment of normally innocuous afferent inputs to the nociceptive pathway is an important aspect of central sensitization.

Figure 5. Spinal disinhibition

Excitatory nociceptive signals are enhanced after nerve injury by a reduction in normal inhibitory regulation through a loss of local inhibitory interneurons, a depolarized anion reversal potential and reduced descending inhibition.

Figure 6. Immune contribution to neuropathic pain

Innate and adaptive immune cells in the periphery and spinal cord can sensitize primary nociceptors and secondary nociceptive neurons respectively to produce pain hypersensitivity.

Figure 7. Individual pathophysiology requires personalized treatment

Etiology, genotype and environmental factors lead to individual pathophysiological changes and individual neuropathic pain profiles. Precise clinical examination and diagnostic tools are a prerequisite to define the pain phenotype and then to use this to identify personalized treatment options.