Pain mechanisms in chronic pancreatitis: of a master and his fire

Abstract

Background: Unraveling the mechanisms of pain in chronic pancreatitis (CP) remains a true challenge. The rapid development of pancreatic surgery in the twentieth century, usage of advanced molecular biological techniques, and emergence of clinician-scientists have enabled the elucidation of several mechanisms that lead to the chronic, complicated neuropathic pain syndrome in CP. However, the proper analysis of pain in CP should include three main arms of mechanisms: "peripheral nociception," "peripheral/pancreatic neuropathy and neuroplasticity," and "central neuropathy and neuroplasticity."

Discussion: According to our current knowledge, pain in CP involves sustained sensitization of pancreatic peripheral nociceptors by neurotransmitters and neurotrophic factors following neural damage. This peripheral pancreatic neuropathy leads to intrapancreatic neuroplastic alterations that involve a profound switch in the autonomic innervation of the human pancreas via "neural remodeling." Furthermore, this neuropathy entails a hyperexcitability of spinal sensory second-order neurons, which are subject to modulation from the brainstem via descending facilitation. Finally, viscerosensory cortical areas react to this central sensitization via spatial reorganization and thus a central neuroplasticity. The present review summarizes the current findings in these arms of mechanisms and introduces a novel concept to consistently describe pain in CP as a "predominantly neuropathic," "mixed-type" pain.

Fig. 1

Main actors in the generation of pain in chronic pancreatitis (CP). The neuropathic pain syndrome in CP involves numerous molecular and morphological alterations at intrapancreatic (peripheral) and extrapancreatic (dorsal root ganglia/DRG, spinal cord, brainstem, and cerebrum) sites. The increased presence of nociceptive signals in the periphery as mediated by neurotransmitters and neurotrophic factors is paralleled by prominent neural damage and numerous intrapancreatic neuropathic/neuroplastic alterations. At the same time, DRG and spinal cord neurons exhibit a hypersensitive state which is subject to modulation from the brainstem over descending facilitation. Finally, the cerebral cortex adapts to these caudal alterations by increasing its basal activity and changing its spatial conformation in viscerosensory areas. Please refer to the manuscript for further details and the respective references