Chronic inflammatory pain is associated with increased excitability and hyperpolarization-activated current ( I h) in C- but not Aδ-nociceptors

Abstract

Inflammatory pain hypersensitivity results partly from hyperexcitability of nociceptive (damage-sensing) dorsal root ganglion (DRG) neurons innervating inflamed tissue. However, most of the evidence for this is derived from experiments using acute inflammatory states. Herein, we used several approaches to examine the impact of chronic or persistent inflammation on the excitability of nociceptive DRG neurons and on their expression of I(h) and the underlying hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which regulate neuronal excitability. Using in vivo intracellular recordings of somatic action potentials from L4/L5 DRG neurons in normal rats and rats with hindlimb inflammation induced by complete Freund's adjuvant (CFA), we demonstrate increased excitability of C- but not Aδ-nociceptors, 5 to 7 days after CFA. This included an afterdischarge response to noxious pinch, which may contribute to inflammatory mechanohyperalgesia, and increased incidence of spontaneous activity (SA) and decreased electrical thresholds, which are likely to contribute to spontaneous pain and nociceptor sensitization, respectively. We also show, using voltage clamp in vivo, immunohistochemistry and behavioral assays that (1) the inflammation-induced nociceptor hyperexcitability is associated, in C- but not Aδ-nociceptors, with increases in the mean I(h) amplitude/density and in the proportion of I(h) expressing neurons, (2) increased proportion of small DRG neurons (mainly IB4-negative) expressing HCN2 but not HCN1 or HCN3 channel protein, (3) increased HCN2- immunoreactivity in the spinal dorsal horn, and (4) attenuation of inflammatory mechanoallodynia with the selective I(h) antagonist, ZD7288. Taken together, the findings suggest that C- but not Aδ-nociceptors sustain chronic inflammatory pain and that I(h)/HCN2 channels contribute to inflammation-induced C-nociceptor hyperexcitability.

Genesis of anxiety, depression, and ongoing abdominal discomfort in ulcerative colitis-like colon inflammation

“…The frequency of spontaneous activity in naïve rats ranges from ϳ0.3 Hz to 1.0 Hz. (32,36). Colon inflammation increased this frequency to ϳ2 Hz in our study, while modified spinal nerve axotomy/nerve ligation increased it to about 4 Hz.…”

“…By contrast, the discharge frequency of evoked action potentials is several-fold greater (10 to 30 Hz in colon afferents and 10 to 120 Hz in dorsal horn neurons at various distension pressures). It is likely that other parameters of spontaneous activity, such as the recruitment of different types of afferent fibers, (C and A␦, A␤ fibers) (8,17,32,35) and their differential projection sites in the brain structures also play a role in inducing specific neuropathies in clinical diseases, such as autoimmune diseases, metabolic disease, cardiovascular disease, and cancer. Each disease or type of injury (4) induces a unique profile of inflammatory mediators (cytokines, chemokines, free radicals, iNOS, and metabolites of arachidonic acid) and, therefore, the nerve lesion and the resulting modifications of afferent neurons to induce different neuropathies.…”

Contribution of hyperpolarization-activated channels to heat hypersensitivity and ongoing activity in the neuritis model

“…Although there have been other studies that have examined the functional role of HCN channels in neuropathic pain, these previous studies have mainly utilized animal models that involve axonotmesis, e.g. SNL and CCI (Chaplan et al, 2003;Lee et al, 2005;Sun et al, 2005;Luo et al, 2007;Jiang et al, 2008;Emery et al, 2011) or chronic hind limb inflammation (Weng et al, 2012).…”

“…Although ZD7288 was not applied directly to the nerve in behavioral experiments, previous studies have shown that <10 mg/kg doses of ZD7288 administered by intravenous infusion rapidly suppress A-fiber ongoing activity within 10 min in the SNL model (Lee et al, 2005) and C-fiber ongoing activity in a model of chronic hind limb inflammation (Weng et al, 2012). Based on the current data, as well as these previous studies, we have therefore proposed that the reversal of heat hypersensitivity by ZD7288 may be due to a partial reduction in C-fiber ongoing activity.…”

“…Since ZD7288 also reduces ongoing activity from A-fiber neurons in these models (Chaplan et al, 2003;Lee et al, 2005 Jiang et al, 2008), it is hypothesized that the drug reverses mechanical hypersensitivity by decreasing the peripheral input into the spinal cord. The contribution of HCN channels to neuronal excitability also extends to unmyelinated axons, as ZD7288 is reported to attenuate C-fiber ongoing activity in a model of chronic hind limb inflammation (Weng et al, 2012).…”