Calcitonin gene-related peptide partially mediates nociception in acute experimental pancreatitis.
ABSTRACT The mechanism by which pancreatitis causes pain is unknown. The neuropeptide calcitonin gene-related peptide (CGRP) is released after sensory nerve activation and promotes nociceptive signaling in models of visceral pain. We hypothesized that acute pancreatitis leads to the activation of pancreatic sensory neurons that release CGRP in the dorsal horn of the spinal cord. This signal is ultimately transmitted to the brain, and pain is sensed.
To induce pancreatitis, rats were injected with l-arginine (500 mg/kg) intraperitoneally or saline (control). Pancreatitis was confirmed by measuring serum amylase and evaluating pancreatic histology. Activation of nociceptive pathways was evaluated by counting Fos-like immunoreactive nuclei (FLI) in the dorsal horn of the spinal cord at T3-L1. Some animals received the CGRP antagonist CGRP(8-37) (50 microg intrathecally) 2 hours before perfusion. Animals were compared using a 2-tailed t test.
l-Arginine treatment induced acute necrotizing pancreatitis in the rat at 24 hours. l-Arginine (24 hours) increased FLI in the dorsal horn of the spinal cord, with a peak effect at L1. Intrathecal administration of CGRP(8-37) significantly decreased the number of FLI nuclei in the dorsal horn of the spinal cord in T11-L1.
Nociception in the l-arginine model of acute pancreatitis is partially mediated by the release of CGRP in the dorsal horn of the spinal cord. Antagonism of CGRP or its receptors may be useful in treating pain from acute pancreatitis.
- [Show abstract] [Hide abstract]
ABSTRACT: Small unmyelinated fibers are the primary afferents by which input initiated by high intensity thermal and mechanical stimuli or by chemical products generated secondary to tissue injury, is communicated to the spinal cord. Events which increase small afferent terminal excitability and neurotransmitter release enhance the nociceptive message, while events which diminish small afferent terminal excitability/release diminish the magnitude of the post-synaptic depolarization and attenuate the pain message. The regulation of the activity of small afferent terminals which contain and release SP at the spinal level can be reasonably interpreted as representing effects (direct or indirect) on this family of peptidergic C-fiber terminals. Thus, SP release provides a well-defined model system for characterizing modulatory components involved in the in vivo regulation of pain behavior at this critical first order link.12/2008: pages 109-138;
- [Show abstract] [Hide abstract]
ABSTRACT: Pain management of many pancreatic diseases remains a major clinical concern. This problem reflects our poor understanding of pain signaling from the pancreas. This review provides an overview of our current knowledge, with emphasis on current pain management strategies and recent experimental findings. A systematic search of the scientific literature was carried out using EMBASE, PubMed/MEDLINE, and the Cochrane Central Register of Controlled Trials for the years 1965-2011 to obtain access to all publications, especially randomized controlled trials, systematic reviews, and meta-analyses exploring pain and its management in disease states such as acute pancreatitis (AP), chronic pancreatitis (CP) and pancreatic cancer (PC). Over the last decade, numerous molecular mediators such as nerve growth factor and the transient receptor potential (TRP) cation channel family have been implicated in afferent nerve signaling. More recent animal studies have indicated the location of the receptive fields for the afferent nerves in the pancreas and shown that these are activated by agents including cholecystokinin octapeptide, 5-hydroxytryptamine and bradykinin. Studies with PC specimens have shown that neuro-immune interactions occur and numerous agents including TRP cation channel V1, artemin and fractalkine have been implicated. Experimental studies in the clinical setting have demonstrated impairment of inhibitory pain modulation from supraspinal structures and implicated neuropathic pain mechanisms. Our knowledge in this area remains incomplete. Characterization of the mediators and receptors/ion channels on the sensory nerve terminals are required in order to facilitate the development of new pharmaceutical treatments for AP and CP.Pancreatology 03/2012; 12(2):104-12. · 2.50 Impact Factor