Pathophysiologic mechanisms of neuropathic pain

Abstract

New animal models of peripheral nerve injury have facilitated our understanding of neuropathic pain mechanisms. Nerve injury increases expression and redistribution of newly discovered sodium channels from sensory neuron somata to the injury site; accumulation at both loci contributes to spontaneous ectopic discharge. Large myelinated neurons begin to express nociceptive substances, and their central terminals sprout into nociceptive regions of the dorsal horn. Descending facilitation from the brain stem to the dorsal horn also increases in the setting of nerve injury. These and other mechanisms drive various pathologic states of central sensitization associated with distinct clinical symptoms, such as touch-evoked pain.

Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets

“…The explained plastic changes in spinal nociceptive neurons are known as 'central sensitization'. 26,27 The aforementioned neurotransmitters interact with N-methyl-D-aspartate receptor (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), metabotropic receptors of glutamate (mGluR), neurokinin-1 receptor (NK1R) and purinergic receptors (P2X) of spinal nociceptive projection neurons [28][29][30][31][32][33][34][35] causing their depolarization and the generation of painful signals to be scattered throughout the nociceptive spinothalamic pathway. In turn, this chemical neurotransmission causes an influx of calcium ions in the spinal nociceptive neurons of second order, 36 a process that activates calcium-dependent intracellular cascades, inducing phosphorylation sensitization 37 and ionic channel and membrane receptor overexpression (Table 3).…”

Neuropeptide Y acts at Y1 receptors in the rostral ventral medulla to inhibit neuropathic pain

“…Much of this research stems from the development of new animal models of peripheral nerve injury (Taylor 2001). These models share some important characteristics, such as mechanical allodynia, ectopic firing, and changes in the primary afferent expression of various peptides and neurotransmitter receptors.…”

Epigenetic Gene Silencing Underlies C-Fiber Dysfunctions in Neuropathic Pain

“…The molecular mechanisms underlying positive symptoms have been extensively investigated (Devor, 2006;Costigan et al, 2009); however, those underlying negative symptoms are much less well understood. A possible mechanism for negative symptoms is a dysfunction of small-diameter (C)-fibers (Taylor, 2001;Devigili et al, 2008;Costigan et al, 2009), such as a loss of C-fiber terminals, an impairment of C-fiber-mediated axon-reflex flare responses, or an increase in the threshold against C-fiber-specific stimuli (Fields et al, 1998;Ueda, 2008). Such C-fiber dysfunctions have been implicated in the manifestation of positive symptoms as well as of negative ones, possibly through a synaptic reorganization in the spinal dorsal horn (Taylor, 2001;Ueda, 2008;Costigan et al, 2009).…”

“…A possible mechanism for negative symptoms is a dysfunction of small-diameter (C)-fibers (Taylor, 2001;Devigili et al, 2008;Costigan et al, 2009), such as a loss of C-fiber terminals, an impairment of C-fiber-mediated axon-reflex flare responses, or an increase in the threshold against C-fiber-specific stimuli (Fields et al, 1998;Ueda, 2008). Such C-fiber dysfunctions have been implicated in the manifestation of positive symptoms as well as of negative ones, possibly through a synaptic reorganization in the spinal dorsal horn (Taylor, 2001;Ueda, 2008;Costigan et al, 2009). Representative examples for negative symptoms were observed with long-lasting downregulations of Na v 1.8 sodium channel and -opioid receptor (MOP) in C-fibers (Waxman et al, 1999;Rashid et al, 2004;Kohno et al, 2005), which are essential for C-fiber functions in terms of determining pain thresholds (Akopian et al, 1999) and for the pharmacological actions of -opioids (Dickenson and Kieffer, 2006), respectively.…”