Sensory Nerves and Chronic Pancreatitis
Introduction
Chronic pancreatitis (CP) is an irreversible and progressive disease characterized by destruction of acinar cells and irregular fibrosis in the pancreas [1,2]. The most frequent and serious clinical symptom is abdominal pain, which occurs in at least 75% of patients. Recurrent or protracted abdominal pain in CP is often difficult to manage and occasionally decreases patient quality of life. Additionally, the mechanism of pain generation in patients with CP is poorly understood. The potential sources of pain in CP include increased pressure within the pancreatic ducts and tissues resulting from pancreatic stones or strictures of the pancreatic duct, pancreatic ischemia, pancreatic fibrosis, and pancreatic pseudocysts [3]. Another possible pain etiology seems to be associated with histological alteration of intrapancreatic neuronal structures. Bockman et al. reported that intrapancreatic nerve fibers in patients become significantly thicker and more numerous during the development of CP [4]. Furthermore, increased immunoreactivity for two sensory neurotransmitters, substance P (SP) and calcitonin gene-related peptide (CGRP), in numerous intrapancreatic nerves has been demonstrated in patients with CP [5]. Previously, in a dye tracing study, we found that axonal branching in primary sensory neurons innervating the pancreas is increased in WBN/Kob rats, a model of human CP; this hyperbranching was found to cause pain in another c-Fos functional tracing and behavioral study [6]. Based on these observations, it has been suggested that alteration of the nervous system, especially primary sensory neurons, in the pancreas likely plays a role in the generation of pain in CP.
The nociceptive information generated in the periphery is transmitted to the central nervous system via the dorsal horn of the spinal cord [7]. Additionally, stimulation of primary sensory neurons causes the release of several neuropeptides, including SP and CGRP, from peripheral nerve endings via axonal reflexes [8,9]. The release of these neuropeptides, especially that of SP, induces local vasodilatation, plasma extravasation, edema formation, and leukocyte infiltration in a phenomenon termed neurogenic inflammation. Furthermore, SP is also known to activate immune cells to produce cytokines, which can exacerbate inflammatory responses [10]. The neurogenic mechanisms of inflammation appear to play a role in determining the severity of acute pancreatitis [11].
Our previous murine study demonstrated that primary sensory denervation by neonatal capsaicin administration histologically attenuated glandular atrophy, pseudotubular complexes, and fibrosis in the pancreas in experimental cases of dibutyltin dichloride-induced CP [12]. This result suggests that the activation of primary sensory neurons induced by pancreatic tissue injury results in the release of pro-inflammatory neuropeptides, leading to deleterious effects in CP. Therefore, modulating the activity of pancreatic sympathetic in CP afferent nerves may not only provide pain relief but may also prevent exacerbation of the inflammatory process in CP.
