Wick, E.C. et al. Transient receptor potential vanilloid 1, calcitonin gene-related peptide, and substance P mediate nociception in acute pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G959-969

Department of Surgery, University of California, San Francisco, San Francisco, California, United States
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 06/2006; 290(5):G959-69. DOI: 10.1152/ajpgi.00154.2005
Source: PubMed


The mechanism of pancreatitis-induced pain is unknown. In other tissues, inflammation activates transient receptor potential vanilloid 1 (TRPV1) on sensory nerves to liberate CGRP and substance P (SP) in peripheral tissues and the dorsal horn to cause neurogenic inflammation and pain, respectively. We evaluated the contribution of TRPV1, CGRP, and SP to pancreatic pain in rats. TRPV1, CGRP, and SP were coexpressed in nerve fibers of the pancreas. Injection of the TRPV1 agonist capsaicin into the pancreatic duct induced endocytosis of the neurokinin 1 receptor in spinal neurons in the dorsal horn (T10), indicative of SP release upon stimulation of pancreatic sensory nerves. Induction of necrotizing pancreatitis by treatment with L-arginine caused a 12-fold increase in the number of spinal neurons expressing the proto-oncogene c-fos in laminae I and II of L1, suggesting activation of nociceptive pathways. L-arginine also caused a threefold increase in spontaneous abdominal contractions detected by electromyography, suggestive of referred pain. Systemic administration of the TRPV1 antagonist capsazepine inhibited c-fos expression by 2.5-fold and abdominal contractions by 4-fold. Intrathecal, but not systemic, administration of antagonists of CGRP (CGRP(8-37)) and SP (SR140333) receptors attenuated c-fos expression in spinal neurons by twofold. Thus necrotizing pancreatitis activates TRPV1 on pancreatic sensory nerves to release SP and CGRP in the dorsal horn, resulting in nociception. Antagonism of TRPV1, SP, and CGRP receptors may suppress pancreatitis pain.

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    • "In L-arginine-induced rat pancreatitis model, there is a great increase in spontaneous abdominal contractions and c-fos expression in spinal neurons. Increases in TRPV1 function and the proportion of pancreatic DRG neurons have been observed in a chronic rat model of pancreatitis, accompanied by visceral hyperalgesia which can be markedly reduced by a TRPV1 antagonist [91, 92]. It has also been shown that siRNA-mediated knockdown of TRPV1 diminishes spontaneous visceral pain in mice [93]. "
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    ABSTRACT: Chronic pain affects billions of lives globally and is a major public health problem in the United States. However, pain management is still a challenging task due to a lack of understanding of the fundamental mechanisms of pain. In the past decades transient receptor potential (TRP) channels have been identified as molecular sensors of tissue damage and inflammation. Activation/sensitization of TRP channels in peripheral nociceptors produces neurogenic inflammation and contributes to both somatic and visceral pain. Pharmacological and genetic studies have affirmed the role of TRP channels in multiple forms of inflammatory and neuropathic pain. Thus pain-evoking TRP channels emerge as promising therapeutic targets for a wide variety of pain and inflammatory conditions.
    Current Neuropharmacology 12/2013; 11(6):652-63. DOI:10.2174/1570159X113119990040 · 3.05 Impact Factor
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    • "Colon Secretory responses induced by distension or H 2 S in guinea-pig and human preparations Attenuation by TRPV1 ablation and antagonism Weber et al., 2001; Krueger et al., 2010 Anus Intractable idiopathic pruritus ani Attenuation by TRPV1 ablation Lysy et al., 2003 Pancreas Chronic pancreatitis induced by trinitrobenzene sulfonic acid in rats Upregulation and sensitization of TRPV1 in pancreas-specific DRG neurons Xu et al., 2007 Pancreas Pancreatitis induced by caerulein in mice Attenuation by TRPV1 antagonism Nathan et al., 2001 Pancreas Acid-evoked injury in a rat model of postendoscopic cholangiopancreatography pancreatitis Attenuation by TRPV1 ablation Noble et al., 2008 Pancreas Islet inflammation in non-obese diabetic mice (genetic model of type I diabetes) Prevention by TRPV1 ablation Razavi et al., 2006; Suri & Szallasi, 2008 Pancreas Pain behavior, referred allodynia/ hyperalgesia and spinal c-Fos expression associated with experimental pancreatitis in rodents Attenuation by TRPV1 antagonism Wick et al., 2006; Xu et al., 2007; Nishimura et al., 2010 Peritoneal cavity Behavioral pain response to intraperitoneal injection of acetic acid or oleoylethanolamide in rodents "
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    ABSTRACT: Approximately 20 of the 30 mammalian transient receptor potential (TRP) channel subunits are expressed by specific neurons and cells within the alimentary canal. They subserve important roles in taste, chemesthesis, mechanosensation, pain and hyperalgesia and contribute to the regulation of gastrointestinal motility, absorptive and secretory processes, blood flow, and mucosal homeostasis. In a cellular perspective, TRP channels operate either as primary detectors of chemical and physical stimuli, as secondary transducers of ionotropic or metabotropic receptors, or as ion transport channels. The polymodal sensory function of TRPA1, TRPM5, TRPM8, TRPP2, TRPV1, TRPV3 and TRPV4 enables the digestive system to survey its physical and chemical environment, which is relevant to all processes of digestion. TRPV5 and TRPV6 as well as TRPM6 and TRPM7 contribute to the absorption of Ca²⁺ and Mg²⁺, respectively. TRPM7 participates in intestinal pacemaker activity, and TRPC4 transduces muscarinic acetylcholine receptor activation to smooth muscle contraction. Changes in TRP channel expression or function are associated with a variety of diseases/disorders of the digestive system, notably gastro-esophageal reflux disease, inflammatory bowel disease, pain and hyperalgesia in heartburn, functional dyspepsia and irritable bowel syndrome, cholera, hypomagnesemia with secondary hypocalcemia, infantile hypertrophic pyloric stenosis, esophageal, gastrointestinal and pancreatic cancer, and polycystic liver disease. These implications identify TRP channels as promising drug targets for the management of a number of gastrointestinal pathologies. As a result, major efforts are put into the development of selective TRP channel agonists and antagonists and the assessment of their therapeutic potential.
    Pharmacology [?] Therapeutics 03/2011; 131(1):142-70. DOI:10.1016/j.pharmthera.2011.03.006 · 9.72 Impact Factor
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    • "This evidence for the activation of nociceptive fibers was further supported by the increased TRPV1 expression and enhanced capsaicin responsiveness of pancreas-specific DRG neurons in their CP model [11]. Furthermore, it is also known that some of the inflammatory mediators stated above can also indirectly activate TRPV1 by lowering its activation threshold [12]. "
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    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.
    Langenbeck s Archives of Surgery 02/2011; 396(2):151-60. DOI:10.1007/s00423-010-0731-1 · 2.19 Impact Factor
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