Article

Transient receptor potential vanilloid 1, calcitonin gene-related peptide, and substance P mediate nociception in acute pancreatitis

Department of Surgery, University of California, San Francisco, San Francisco, California, United States
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.74). 06/2006; 290(5):G959-69. DOI: 10.1152/ajpgi.00154.2005
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
73 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sensory nerves are equipped with receptors and ion channels that allow them to detect and respond to diverse chemical, mechanical, and thermal stimuli. These sensory proteins include G protein-coupled receptors (GPCRs) and transient receptor potential (TRP) ion channels. A subclass of peptidergic sensory nerves express GPCRs and TRP channels that detect noxious, irritant, and inflammatory stimuli. Activation of these nerves triggers protective mechanisms that lead to withdrawal from danger (pain), removal of irritants (itch, cough), and resolution of infection (neurogenic inflammation). The GPCR-TRP axis is central to these mechanisms. Signals that emanate from the GPCR superfamily converge on the small TRP family, leading to channel sensitization and activation, which amplify pain, itch, cough, and neurogenic inflammation. Herein we discuss how GPCRs and TRP channels function independently and synergistically to excite sensory nerves that mediate noxious and irritant responses and inflammation in the skin and the gastrointestinal and respiratory systems. We discuss the signaling mechanisms that underlie the GPCR-TRP axis and evaluate how new information about the structure of GPCRs and TRP channels provides insights into their functional interactions. We propose that a deeper understanding of the GPCR-TRP axis may facilitate the development of more selective and effective therapies to treat dysregulated processes that underlie chronic pain, itch, cough, and inflammation.
    Pharmacological reviews 01/2015; 67(1):36-73. DOI:10.1124/pr.114.009555 · 18.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abdominal pain frequently accompanies inflammatory disorders of the gastrointestinal tract (GIT), and animal models of GIT inflammation have been developed to explore the role of the central nervous system (CNS) in this process. Here, we summarize the evidence from animal studies for CNS plasticity following GIT inflammation. A systematic review was conducted to identify studies that: (1) used inflammation of GIT organs, (2) assessed pain or visceral hypersensitivity, and (3) presented evidence of CNS involvement. Two hundred and eight articles were identified, and 79 were eligible for analysis. Rats were most widely used (76%). Most studies used adult animals (42%) with a bias toward males (74%). Colitis was the most frequently used model (78%) and 2,4,6-trinitrobenzenesulfonic acid the preferred inflammatory agent (33%). Behavioral (58%), anatomical/molecular (44%), and physiological (24%) approaches were used alone or in combination to assess CNS involvement during or after GIT inflammation. Measurement times varied widely (<1 h-> 2 wk after inflammation). Blinded outcomes were used in 42% studies, randomization in 10%, and evidence of visceral inflammation in 54%. Only 3 studies fulfilled our criteria for high methodological quality, and no study reported sample size calculations. The included studies provide strong evidence for CNS plasticity following GIT inflammation, specifically in the spinal cord dorsal horn. This evidence includes altered visceromotor responses and indices of referred pain, elevated neural activation and peptide content, and increased neuronal excitability. This evidence supports continued use of this approach for preclinical studies; however, there is substantial scope to improve study design.
    Inflammatory Bowel Diseases 11/2013; DOI:10.1097/01.MIB.0000437499.52922.b1 · 5.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 2.35 Impact Factor