Role of Capsaicin-Sensitive C-Fiber Afferents in Neuropathic Pain-Induced Synaptic Potentiation in the Nociceptive Amygdala

Abstract

BackgroundNeurons in the capsular part of the central nucleus of the amygdala (CeC), a region also called "nociceptive amygdala," receive nociceptive information from the dorsal horn via afferent pathways relayed from the lateral parabrachial nucleus (LPB). As the central amygdala is known to be involved in the acquisition and expression of emotion, this pathway is thought to play central roles in the generation of affective responses to nociceptive inputs. Excitatory synaptic transmission between afferents arising from the LPB and these CeC neurons is potentiated in arthritic, visceral, neuropathic, inflammatory and muscle pain models. In neuropathic pain models following spinal nerve ligation (SNL), in which we previously showed a robust LPB-CeC potentiation, the principal behavioral symptom is tactile allodynia triggered by non-C-fiber low-threshold mechanoreceptor afferents. Conversely, recent anatomical studies have revealed that most of the spinal neurons projecting to the LPB receive C-fiber afferent inputs. Here, we examined the hypothesis that these C-fiber-mediated inputs are necessary for the full establishment of robust synaptic potentiation of LPB-CeC transmission in the rats with neuropathic pain.ResultsPostnatal capsaicin treatment, which has been shown to denervate the C-fibers expressing transient receptor potential vanilloid type-1 (TRPV1) channels, completely abolished eye-wiping responses to capsaicin eye instillation in rats, but this treatment did not affect mechanical allodynia in the nerve-ligated animals. However, the postnatal capsaicin treatment prevented LPB-CeC synaptic potentiation after SNL, unlike in the vehicle-treated rats, primarily due to the decreased incidence of potentiated transmission by elimination of TRPV1-expressing C-fiber afferents.ConclusionsC-fiber-mediated afferents in the nerve-ligated animals may be a required facilitator of the establishment of nerve injury-evoked synaptic potentiation in the CeC. These inputs might play essential roles in the chronic pain-induced plastic changes in the central network linking nociception and negative emotion.

Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain

“…Excitatory synapses between inputs from the parabrachial area to the central nucleus of amygdala are enhanced in animal models of inflammatory pain 141 and neuropathic pain 142,143 .…”

Neuropeptide S: a novel regulator of pain-related amygdala plasticity and behaviors

“…1). For stimulation of presumed PB inputs (PB-CeLC synapse), the stimulating electrode was positioned under microscopic control on the fiber tract that runs dorsomedial to the CeA and ventral to but outside of the caudate-putamen Nakao et al 2012;Neugebauer et al 2003;Watabe et al 2013). The trajectory of fibers in this pathway and their terminal arborizations in the CeLC have been described previously in great detail (see Fig.…”

“…8). E-S coupling was measured by stimulating synapses that provide direct (PB-CeLC) or indirect (BLA-CeLC) nociceptive input to the CeLC and undergo pain-related plasticity (Ikeda et al 2007;Nakao et al 2012;Neugebauer et al 2004Neugebauer et al , 2009. In all CeLC neurons a monosynaptic EPSC could be evoked by stimulation of inputs from PB or BLA, whereas EC stimulation evoked a polysynaptic IPSC.…”

Functional brain mapping using specific sensory-circuit stimulation and a theoretical graph network analysis in mice with neuropathic allodynia

“…Previous studies have identified a brain region termed the ‘pain matrix’ in humans, which includes the thalamus, the posterior and anterior insula, the secondary somatosensory cortex, the ACA, the periaqueductal gray matter, the central nucleus of the amygdala, and other regions3132333435. In these regions, pain signaling pathways are classified into two major systems: a lateral nociceptive system based on the cortical projections of the lateral thalamic nuclei to S1 and S2 and a medial nociceptive system based on the medial thalamic group of nuclei with ACA projections3637.…”