Reappraising neuropathic pain in humans—how symptoms help disclose mechanisms

Abstract

Neuropathic pain--that is, pain arising directly from a lesion or disease that affects the somatosensory system--is a common clinical problem, and typically causes patients intense distress. Patients with neuropathic pain have sensory abnormalities on clinical examination and experience pain of diverse types, some spontaneous and others provoked. Spontaneous pain typically manifests as ongoing burning pain or paroxysmal electric shock-like sensations. Provoked pain includes pain induced by various stimuli or even gentle brushing (dynamic mechanical allodynia). Recent clinical and neurophysiological studies suggest that the various pain types arise through distinct pathophysiological mechanisms. Ongoing burning pain primarily reflects spontaneous hyperactivity in nociceptive-fibre pathways, originating from 'irritable' nociceptors, regenerating nerve sprouts or denervated central neurons. Paroxysmal sensations can be caused by several mechanisms; for example, electric shock-like sensations probably arise from high-frequency bursts generated in demyelinated non-nociceptive Aβ fibres. Most human and animal findings suggest that brush-evoked allodynia originates from Aβ fibres projecting onto previously sensitized nociceptive neurons in the dorsal horn, with additional contributions from plastic changes in the brainstem and thalamus. Here, we propose that the emerging mechanism-based approach to the study of neuropathic pain might aid the tailoring of therapy to the individual patient, and could be useful for drug development.

Capsaicin 8% patch versus oral pregabalin in patients with peripheral neuropathic pain

“…The majority of RCTs in PNP have included patients with PHN or diabetic peripheral neuropathy (DPN) as experimental models, the results of which are translated to other types of PNP. This study highlights the subtle differences that can occur in response to treatment across different types of PNP and the need to personalize treatment to individual patient needs, as suggested by many theoretical studies (Truini et al, 2013). …”

“…Aetiologies range from mechanical and inflammatory diseases to injury and nerve compression (Hall et al., 2006). A key pathophysiological mechanism is neuronal hyperexcitability, both within the axon and cell body as well as peripheral nociceptors (Truini et al., 2013). This allows for single or combined therapies targeting one or more sites within the neurone.…”

Schwann cell interactions with axons and microvessels in diabetic neuropathy

“…This localization implies that aldose reductase dysfunction does not only alter vascular function, although this observation has led to something of a conundrum with regard to the pathogenic role of the enzyme: demyelination can be a feature of human diabetic neuropathy 28,43 , but diabetic rodents rarely exhibit marked Schwann cell pathology Diabetic neuropathy classically presents as a sensory neuropathy that results from damage to both large and small fibres, which can cause negative symptoms, such as loss of sensation to touch, vibration, pinprick, hot and cold 177,178 , and positive symptoms, such as paradoxical pain and hypersensitivity [179][180][181][182][183] . Negative and positive symptoms are both most pronounced distally, with a characteristic stocking-glove pattern (see the figure).…”

Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain

“…Although designated somatosensory neurons and spinal cord circuits exist for mediating pain sensation, they are modulated by other somatosensory pathways for normal perception (Ma, 2012). Specifically, Aβ low-threshold mechanoreceptors (Abraira and Ginty, 2013;Fleming and Luo, 2013), which innervate deep DH (dDH) layers (III through V) of the spinal cord and mediate light touch sensation, have been considered important players in nociceptive modulation and mechanical allodynia (Campbell et al, 1988;Truini et al, 2013). A prominent idea is the "gate control theory" of pain (GCT) ( Figure 1A), which proposes that some DH inhibitory interneurons (gating neurons) receive excitatory inputs from large-diameter (A) touch-sensing afferents and inhibitory inputs from small-diameter (C) pain-sensing afferents, and that the activation of these gating neurons inhibits transmission of both pain and touch pathways to the DH nociceptive projection neurons (Melzack and Wall, 1965).…”