Mechanism Of Pain In Chronic Pancreatitis Research Articles

Dysfunctional astrocyte glutamate uptake in the hypothalamic paraventricular nucleus contributes to visceral pain and anxiety-like behavior in mice with chronic pancreatitis.

Abdominal visceral pain is a predominant symptom in patients with chronic pancreatitis (CP); however, the underlying mechanism of pain in CP remains elusive. We hypothesized that astrocytes in the hypothalamic paraventricular nucleus (PVH) contribute to CP pain pathogenesis. A mouse model of CP was established by repeated intraperitoneal administration of caerulein to induce abdominal visceral pain. Abdominal mechanical stimulation, open field and elevated plus maze tests were performed to assess visceral pain and anxiety-like behavior. Fiber photometry, brain slice Ca2+ imaging, electrophysiology, and immunohistochemistry were used to investigate the underlying mechanisms. Mice with CP displayed long-term abdominal mechanical allodynia and comorbid anxiety, which was accompanied by astrocyte glial fibrillary acidic protein reactivity, elevated Ca2+ signaling, and astroglial glutamate transporter-1 (GLT-1) deficits in the PVH. Specifically, reducing astrocyte Ca2+ signaling in the PVH via chemogenetics significantly rescued GLT-1 deficits and alleviated mechanical allodynia and anxiety in mice with CP. Furthermore, we found that GLT-1 deficits directly contributed to the hyperexcitability of VGLUT2PVH neurons in mice with CP, and that pharmacological activation of GLT-1 alleviated the hyperexcitability of VGLUT2PVH neurons, abdominal visceral pain, and anxiety in these mice. Taken together, our data suggest that dysfunctional astrocyte glutamate uptake in the PVH contributes to visceral pain and anxiety in mice with CP, highlighting GLT-1 as a potential therapeutic target for chronic pain in patients experiencing CP.

Management of Chronic Pancreatitis

Chronic pancreatitis (CP) is a syndrome that is characterized by inflammation, irreversible fibrosis, and loss of acinar and islet cells. It has also been described as an “enigmatic process of uncertain pathogenesis, unpredictable clinical course, and unclear treatment.” This review describes the epidemiology, diagnosis, diagnostic challenges, differential diagnosis, treatment, complications, and clinical course and prognosis of CP, as well as future challenges. Figures show a computed tomographic (CT) scan of calcific CP, a secretin-enhanced magnetic resonance cholangiopancreatogram showing a dilated and tortuous main pancreatic duct, a CT scan of a large chronic pseudocyst compressing the stomach and pancreas, an endoscopic ultrasound (EUS) image of CP, a retrograde pancreatogram showing a dilated main pancreatic duct with stones and “blunted” side branches, sources of pain in CP, neuropathic pain mechanisms in CP, and an algorithm summarizing treatment of pain in CP. Tables list the TIGAR-O etiologic classification of CP, standard criteria for diagnosis of CP by EUS, Cambridge endoscopic retrograde cholangiopancreatography grading for CP, and a stepwise radiographic and endoscopic diagnostic approach to patients with suspected CP. Key words: bile duct obstruction, chronic pancreatitis, pancreatic calcifications, TIGAR-O system This review contains 8 highly rendered figures, 4 tables, and 54 references.

Current Surgical Treatment for Chronic Pancreatitis

Chronic pancreatitis (CP) is a painful, yet benign inflammatory process of the pancreas. Surgical management should be individualized because the pain is multifactorial and its mechanisms vary from patient to patient. Two main pathogenetic theories for the mechanisms of pain in CP have been proposed: the neurogenic theory and the theory of increased intraductal/intraparenchymal pressures. The latter theory is strongly supported by the good results of drainage procedures in the surgical management of CP. Other possible contributing factors include pancreatic ischemia; a centrally sensitized pain state; and the development of complications, such as pseudocysts and stenosis of the duodenum or common bile duct. Common indications for surgery include intractable pain, suspicion of neoplasm, and complications that cannot be resolved with radiological or endoscopic treatments. Operative procedures have been historically classified into 4 categories: decompression procedures for diseased and obstructed pancreatic ducts; resection procedures for the proximal, distal, or total pancreas; denervation procedures of the pancreas; and hybrid procedures. Pancreaticoduodenectomy and pylorus-preserving pancreaticoduodenectomy, once the standard operations for patients with CP, have been replaced by hybrid procedures, such as duodenum-preserving pancreatic head resection, the Frey procedure, and their variants. These procedures are safe and effective in providing long-term pain relief and in treating CP-related complications. Hybrid procedures should be the operations of choice for patients with CP.

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

BackgroundUnraveling 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.”DiscussionAccording 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.

Mechanisms and Natural History of Pain in Chronic Pancreatitis

Pain is a major clinical manifestation of chronic pancreatitis (CP) and a common indication for surgery in these patients. Pathogenesis of pain in CP is multifactorial and the mechanisms of pain may differ from patient to patient. This can explain why one therapeutic method of treatment of pain does not work in all patients and in different stages of the disease. Two main complimentary pathogenetic theories have been proposed to explain the mechanisms of pain in CP, the neurogenic theory and the theory of increased intraductal/intraparenchymal pressures. According to the neurogenic theory, in CP there are alterations of pancreatic/peripancreatic nerves, exposing them to noxious substances and/or activated immune cells, thereby generating pain ("neuroimmune interaction"). The other theory of intraductal/intraparenchymal hypertension suggests that pain in CP is generated as a result of increased pressures within the pancreatic ductal system and/or pancreatic parenchyma, like the pain in the classic compartment syndrome. The theory of intraductal/intraparenchymal hypertension is strongly supported by the good results of drainage procedures in the surgical management of CP. Pancreatic ischemia, oxygen-free radicals, centrally sensitized pain state, acute exacerbations of CP, development of complications from the pancreas (most commonly, pseudocysts) or adjacent organs (usually, duodenal and/or common bile duct stenosis), etc. are other possible contributing factors. Different patterns of pain have been described in idiopathic (early vs. late onset) and in alcoholic CP. Interestingly, pain is automatically relieved during the natural course of the disease in some patients (the "burn-out" phenomenon), after a relatively long time (from a few years to up to 3 decades). However, this is an unpredictable evolution for the individual patient. Therefore, surgery should be offered when pain is intense and after failure of conservative treatment. Surgical management should be individualized, depending on the particular findings of each patient. The knowledge of the pathophysiologic basis and of natural course of pain in CP is of paramount importance for the surgeon to select appropriate therapy for the individual patient with CP.

Assessment of Experimental Pain From Skin, Muscle, and Esophagus in Patients With Chronic Pancreatitis

Comprehensive experimental methods are of major relevance assessing pain mechanisms in patients with chronic pain. Chronic pancreatitis is thought to involve the sensory response in other visceral organs and somatic tissue. We, therefore, aimed at exploring the pain mechanisms in chronic pancreatitis (CP) using a multimodal and multitissue stimulation approach. Ten patients (mean age, 50 years) with CP and 13 healthy controls (mean age, 35 years) participated. None of the patients took analgesics regularly. All were exposed to multimodal (mechanical, thermal, and electrical) experimental pain in the skin, muscles, and esophagus. The patients were hyposensitive to mechanical stimulations of the skin (P = 0.001), but there were no differences in the pain to thermal and electrical stimulations. In the muscle and esophagus, no differences in pain thresholds were found. The difference between single and repeated stimulations reflecting the degree of central sensitization was 17% in controls and 36% in patients (P = 0.001). The referred pain area to electrical stimulation was 30.1 cm2 in the patients and 7.7 cm2 for the controls (P = 0.02). The findings suggest that the balance among central hyperexcitability, neuroplastic changes, and descending pain-modulating pathways may explain the pain response to experimental multimodal stimulations in CP. This will likely also reflect the clinical pain mechanisms and may have important impact in selection of treatment, where drugs with potential effects on these mechanisms should be used.

Enhanced excitability and suppression of A-type K+ current of pancreas-specific afferent neurons in a rat model of chronic pancreatitis

Chronic pancreatitis (CP) is a relatively common disorder, characterized by glandular insufficiency and chronic, often intractable, pain. The mechanism of pain in CP is poorly understood. We have previously developed a model of trinitrobenzene sulphonic acid (TNBS)-induced CP that results in nociceptive sensitization in rats. This study was designed to examine changes in the excitability and alteration of voltage-gated K(+) currents of dorsal root ganglia (DRG) neurons innervating the pancreas. CP was induced in adult rats by an intraductal injection of TNBS. DRG neurons innervating the pancreas were identified by 1,1'-dioleyl-3,3,3',3-tetramethylindocarbocyanine methanesulfonate fluorescence labeling. Perforated patch-clamp recordings were made from acutely dissociated DRG neurons from control and TNBS-treated rats. Pancreas-specific DRG neurons displayed more depolarized resting potentials in TNBS-treated rats than those in controls (P < 0.02). Some neurons from the TNBS-treated group exhibited spontaneous firings. TNBS-induced CP also resulted in a dramatic reduction in rheobase (P < 0.05) and a significant increase in the number of action potentials evoked at twice rheobase (P < 0.05). Under voltage-clamp conditions, neurons from both groups exhibited transient A-type (I(A)) and sustained outward rectifier K(+) currents (I(K)). Compared with controls, the average I(A) but not the average I(K) density was significantly reduced in the TNBS-treated group (P < 0.05). The steady-state inactivation curve for I(A) was displaced by approximately 20 mV to more hyperpolarized levels after the TNBS treatment. These data suggest that TNBS treatment increases the excitability of pancreas-specific DRG neurons by suppressing I(A) density, thus identifying for the first time a specific molecular mechanism underlying chronic visceral pain and sensitization in CP.

Hypoalgesia to experimental visceral and somatic stimulation in painful chronic pancreatitis

To gain more information of the pain mechanisms in chronic pancreatitis we applied standardized experimental pain stimulation of the duodenum, oesophagus and the skin in 12 healthy controls and 13 patients with chronic pancreatitis and typical pain attacks. Using endoscopy a guide wire was positioned into the horizontal part of the duodenum, and a probe with a distal balloon was introduced over the guide wire. Mechanical stimuli were given as tonic (38 ml/min) or phasic (increasing volume steps of 5 ml delivered for 60 s) distensions of the balloon. After stimulation of the duodenum, the distal oesophagus was stimulated with the same protocol. Finally, the skin was stimulated with 'single and repeated burst' electrical stimuli reflecting activation of peripheral and central pain mechanisms. The stimuli reliably evoked both painful and non-painful local and referred sensations. The patients had hyposensitivity to both tonic and phasic mechanical stimuli of the duodenum and the oesophagus (P=0.001). Hypoalgesia was also observed to single and repeated electrical skin stimuli in the patients, most evident for repeated stimuli (P=0.001). The evoked referred pain did not differ between the groups, but the patients used on average more words from the McGill Pain Questionnaire to describe the pain evoked in the duodenum (P=0.02). Generalized hypoalgesia to experimental visceral and somatic stimulations was found in chronic pancreatitis. The findings suggest that the activation and modulation of central mechanisms is fundamental in pancreatic pain, and future studies should address the effect of analgesics with central effects in the treatment of these patients.

Invited Commentary

Although putative pain mechanisms in chronic pancreatitis remain unproved, considerable circumstantial evidence indicts increased glandular and intraductal pressure secondary to fibrotic ductal strictures and/or obstructing intraductal calculi. Surgical decompression of obstructed ducts by pancreatojejunostomy or various forms of pancreatic resection have relieved pain in 60% to 70% of the patients, many of whom were observed for more than 5 years. Alternative attempts at ductal decompression have been proposed using pancreatic duct stents, transpapillary extraction of calculi (TPE), or fragmentation of intraductal stones with a focused laser or sonic energy (ESWL). Whereas the safety and efficacy of stents is now being questioned, evaluation of the latter approaches continues. Martin et al describe a modest yet well-studied group of 12 patients with intraductal pancreatic calculi who were treated successfully with TPE alone or TPE combined with ESWL and were followed up for an average of 19 months. More extensive experience with ESWL