Identification of the visceral pain pathway activated by noxious colorectal distension in mice.

Department of Human Physiology, Flinders Medical Science and Technology Cluster, Flinders University Adelaide, SA, Australia.
Frontiers in Neuroscience 01/2011; 5:16. DOI: 10.3389/fnins.2011.00016
Source: PubMed

ABSTRACT In patients with irritable bowel syndrome, visceral pain is evoked more readily following distension of the colorectum. However, the identity of extrinsic afferent nerve pathway that detects and transmits visceral pain from the colorectum to the spinal cord is unclear. In this study, we identified which extrinsic nerve pathway(s) underlies nociception from the colorectum to the spinal cord of rodents. Electromyogram recordings were made from the transverse oblique abdominal muscles in anesthetized wild type (C57BL/6) mice and acute noxious intraluminal distension stimuli (100-120 mmHg) were applied to the terminal 15 mm of colorectum to activate visceromotor responses (VMRs). Lesioning the lumbar colonic nerves in vivo had no detectable effect on the VMRs evoked by colorectal distension. Also, lesions applied to the right or left hypogastric nerves failed to reduce VMRs. However, lesions applied to both left and right branches of the rectal nerves abolished VMRs, regardless of whether the lumbar colonic or hypogastric nerves were severed. Electrical stimulation applied to either the lumbar colonic or hypogastric nerves in vivo, failed to elicit a VMR. In contrast, electrical stimulation (2-5 Hz, 0.4 ms, 60 V) applied to the rectum reliably elicited VMRs, which were abolished by selective lesioning of the rectal nerves. DiI retrograde labeling from the colorectum (injection sites 9-15 mm from the anus, measured in unstretched preparations) labeled sensory neurons primarily in dorsal root ganglia (DRG) of the lumbosacral region of the spinal cord (L6-S1). In contrast, injection of DiI into the mid to proximal colon (injection sites 30-75 mm from the anus, measured in unstretched preparations) labeled sensory neurons in DRG primarily of the lower thoracic level (T6-L2) of the spinal cord. The visceral pain pathway activated by acute noxious distension of the terminal 15 mm of mouse colorectum is transmitted predominantly, if not solely, through rectal/pelvic afferent nerve fibers to the spinal cord. The sensory neurons of this spinal afferent pathway lie primarily in the lumbosacral region of the spinal cord, between L6 and S1.

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    ABSTRACT: Presence of metabotropic receptors in dorsal horns of the spinal cord neurons stated that after intraventricular intrathecal use of specific antagonists for mGluR1 receptors reveals analgetic activity both in rodents and large mammals. Knockdown of spinal mGluR1 receptors soothes pain and restores effectiveness of opioids activity after damage of the nerve in rats. Recently published researches proved that mice which were deprived of endothelin-3 in rectum on Hirschprung disease model lose selectively the ability to feel visceral pain. Qi and co-workers, suggest special participation of tension-dependent Na + and Ca2 + channels in visceral pain feeling whereas use of these channels antagonists can contribute to new possibilities in visceral pain therapy. Results of our research interchangeably indicate that used centrally non-specific mGluRgroup I receptor antagonist – which is racemic form of DL-AP3 – impedes transmission of nocifensive impuls induced by 5 min mechanical distension of descending colon wall in sheep. It also prevents from cascade of behavioural, clinical and neuroendocrine phenomena released in sharp visceral pain by mechanical impuls. DL-AP3 can be recommended in soothing of intestines colic symptoms in sheep provided that similar effects after peripheral usage of that racemate will be confirmed. part in transmission of analgesic activity. Usage of mGluR agonistsrevealedthat activation of these receptors in the dorsal horn and finally facilitates pain transmission. Group I receptors are important in hyperalgesia, persistent pain and central post injury sensitization [5]. Activation of group II metabotropic receptors proved to be analgesic and subgroup mGluR 3 was found to play predominant role in transmission of inflammatory pain [6]. Group I receptors are primarily localized as postsynaptic neural cells in brain structures (cerebral cortex, dorsal and ventral striatum, septal area, hippocampus). Metabotropic receptors exist in CNS as well as in enteric nervous system [7] including sensory neurons projecting to the CNS [8] Studies of [5,9] showed that i.c.v. infusion of 2-Methyl-6-Phenylethynyl-Pyridine (MPEP), which is mGluR 5 antagonist, reduces mechanosensitivity of ferret tension receptors activated by gastric distension. Sensory neurons that occur in vagal sensory ganglia innervate gastrointestinal tract. Expression of all kinds of mGluRs has been demonstrated in vagal afferent cells [10]. Several behavioral studies have demonstrated that mGluR 5 in the dorsal horn of the spinal cord play crucial role in visceral, inflammatory and neuropathic pain. Physiopharmacology of visceral pain was proved on a model of mechanical nocifensive impuls emitted by duodenum and/ or colon distension in rodents Lu et al. [11]. The results indicate interchangeably that stretching of an intestine wall is correlated with contraction amplitude of both duodenum and colon. It is also an important impuls for intestines contractility. In Lu et al. [11]. opinion contractility reaction of mice intestine wall for mechanic impulses nervous regulation is involved.
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    ABSTRACT: The present study examined contribution of group I metabotropic glutamate receptors mGluRs to development and maintenance of changes in cortisol and catecholamines blood concentrations caused by visceral pain produced by colonal distension (CD) in sheep. Intracerebroventricular (icv) administration of the group I mGluRs non-selective antagonist DL-2-Amino-3-phosphonopropionic acid (DL-AP3; 4.0 8.0 and/or 12.0 mg in toto), 10 min before, blocked development of vegetative visceral pain symptoms and neuroendocrinological changes in the blood of sheep. This data demonstrated that development and maintenance of visceral pain symptoms of CD is dependent on activation of group I mGluRs in central nervous system (CNS) and that these receptors play a crucial role in modulating of acute colonal pain in sheep.
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    ABSTRACT: In mammals, sensory stimuli in visceral organs, including those that underlie pain perception, are detected by spinal afferent neurons, whose cell bodies lie in dorsal root ganglia (DRG). One of the major challenges in visceral organs has been how to identify the different types of nerve endings of spinal afferents that transduce sensory stimuli into action potentials. The reason why spinal afferent nerve endings have been so challenging to identify is because no techniques have been available, until now, that can selectively label only spinal afferents, in high resolution. We have utilized an anterograde tracing technique, recently developed in our laboratory, which facilitates selective labeling of only spinal afferent axons and their nerve endings in visceral organs. Mice were anesthetized, lumbosacral DRGs surgically exposed, then injected with dextran-amine. Seven days post-surgery, the large intestine was removed. The characteristics of thirteen types of spinal afferent nerve endings were identified in detail. The greatest proportion of nerve endings was in submucosa (32%), circular muscle (25%) and myenteric ganglia (22%). Two morphologically distinct classes innervated myenteric ganglia. These were most commonly a novel class of intraganglionic varicose endings (IGVEs) and occasionally rectal intraganglionic laminar endings (rIGLEs). Three distinct classes of varicose nerve endings were found to innervate the submucosa and circular muscle, while one class innervated internodal strands, blood vessels, crypts of lieberkuhn, the mucosa and the longitudinal muscle. Distinct populations of sensory endings were CGRP-positive. We present the first complete characterization of the different types of spinal afferent nerve endings in a mammalian visceral organ. The findings reveal an unexpectedly complex array of different types of primary afferent endings that innervate specific layers of the large intestine. Some of the novel classes of nerve endings identified must underlie the transduction of noxious and/or innocuous stimuli from the large intestine.
    PLoS ONE 11/2014; 9(11):e112466. · 3.53 Impact Factor

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