Systemic administration of anti-NGF increases A-type potassium currents and decreases pancreatic nociceptor excitability in a rat model of chronic pancreatitis

Abstract

Colak T, Shenoy M, Pasricha PJ. Systemic administration of anti-NGF increases A-type potassium currents and decreases pancreatic nociceptor excitability in a rat model of chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 302: G176 -G181, 2012. First published October 28, 2011 doi:10.1152/ajpgi.00053.2011We have previously shown that pancreatic sensory neurons in rats with chronic pancreatitis (CP) display increased excitability associated with a decrease in transient inactivating potassium currents (I A), thus accounting in part for the hyperalgesia associated with this condition. Because of its well known role in somatic hyperalgesia, we hypothesized a role for the nerve growth factor (NGF) in driving these changes. CP was induced by intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats. After 3 wk, anti-NGF antibody or control serum was injected intra-peritoneally daily for 1 wk. This protocol was repeated in another set of experiments in control rats (receiving intraductal PBS instead of TNBS). Pancreatic nociceptors labeled with the dye Dil were identified, and patch-clamp recordings were made from acutely dissociated DRG neurons. Sensory neurons from anti-NGF-treated rats displayed a lower resting membrane potential, increased rheobase, decreased burst discharges in response to stimulatory current, and decreased input resistance compared with those treated with control serum. Under voltage-clamp condition, neuronal I A density was increased in anti-NGF-treated rats compared with rats treated with control serum. However, anti-NGF treatment had no effect on electrophysiological parameters in neurons from control rats. The expression of Kvassociated channel or ancillary genes Kv1.4, 4.1, 4.2, 4.3, and DPP6, DPP10, and KCHIPs 1-4 in pancreas-specific nociceptors was examined by laser-capture microdissection and real-time PCR quantification of mRNA levels. No significant differences were seen among those. These findings emphasize a key role for NGF in maintaining neuronal excitability in CP specifically via downregulation of I A by as yet unknown mechanisms. dorsal root ganglion; trinitrobenzene sulfonic acid; chronic pancreatitis; excitability; transient A-type potassium current A CARDINAL SYMPTOM OF chronic pancreatitis (CP) is pain, which is also one of the most difficult to treat, a fact that reflects our inadequate understanding of its pathogenesis (1). In recent years, however, some progress has been made in this area, aided by the development of a robust and reproducible rat model of painful CP with construct, face, and predictive validity (19). Using this model, we have demonstrated that CP results in the sensitization of pancreatic nociceptors, with increased spontaneous firings and excitability (22). We therefore postulated that, as with other painful inflammatory conditions, CP caused an increased "afferent barrage" from sensitized primary neurons with amplification and persistence of pain (2). Our studies also suggested an ionic basis for these changes as we found a signi...

Neural plasticity in pancreatitis and pancreatic cancer

“…For chronic pancreatitis, infusion of trinitrobenzene sulphonic acid (TNBS) into the pancreatic duct was used in several studies to investigate chronic-pancreatitisassociated neural alterations, particularly within the DRG. [62][63][64][65] By means of this model, substance P, CGRP, TRPV1, and the density of ion currents were shown to be augmented in the thoracic DRG that supply the pancreas, [62][63][64][65] and NGF was reported to be upregulated within the pancreas, 62 which has been previously shown in human chronic pancreatitis. 66 Electrophysiologically, the pancreas-innervating thoracic DRG neurons were reported to be hyperexcitable in the same model due to suppression of A type I (A) currents, 65 and this suppression and nociception were reversible upon systemic administration of anti-NGF antibodies.…”

“…66 Electrophysiologically, the pancreas-innervating thoracic DRG neurons were reported to be hyperexcitable in the same model due to suppression of A type I (A) currents, 65 and this suppression and nociception were reversible upon systemic administration of anti-NGF antibodies. 64 Furthermore, retrograde tracing of pancreatic nerve fibres and anterograde tracing of DRG neurites in spontaneous chronic pancreatitis in the Wistar Bonn/Kobori (WBN/Kob) rat model showed that the amount of retrograde labelled DRG neurons decreased and the numbers of anterograde labelled nerve fibres in the pancreas increased during chronic pancreatitis. 67 Hence, evidence for altered and enhanced activity of sensory DRG neurons in chronic pancreatitis models exists.…”

Transforming Growth Factor Beta Induces Sensory Neuronal Hyperexcitability, and Contributes to Pancreatic Pain and Hyperalgesia in Rats with Chronic Pancreatitis

“…Conversely, TGFβ1 antagonism can attenuate hypersensitivity and hyperalgesia in chronic pancreatitis, a painful inflammatory condition. These studies do not imply that TGFβ is the sole or even dominant contributor to nociceptive sensitization in chronic pancreatitis, where many other factors, such as NGF may also play a role [30,31]. Surprisingly, TGFβ antagonism caused hyperalgesia to noxious stimulation in naïve rats, suggesting that endogenous TGF plays a tonic modulatory effect in nociception signal processing and that the effects of TGF on nociception are likely to be complex and bimodal, as has been described for other biological consequences of TGF neutralization [32].…”

Upregulation of Nav1.7 Through High Salt Loading

“…21 These findings emphasize a crucial role of Na v 1.7 protein which is dynamic and up-regulated in response to increased stresses. Similarly, the other cellular molecules such as KCNA4 22 and TRPV1 23 and cellular endogenous factors such as neural growth factor 23 and transforming growth factor 24 have been reported in relation to visceral hypersensitivity. Obviously, the present findings in which the molecules of Na v 1.7, Na v 1.8, KCNA4 and TRPV1 have been suggested to be associated with visceral hypersensitivity need for the further assessment under high salt feeding, based on the idea reported from Black et al 16 …”