Responses of rat spinal neurons to distension of inflamed colon: role of tachykinin NK2 receptors

Laird, Jennifer M.A.; Olivar, Teresa; López-García, J.A.; Maggi, Carlo Alberto; Cerveró, Fernando

doi:10.1016/s0028-3908(00)00205-7

Cited by 44 publications

(27 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is consistent with previous observations demonstrating that physiological distension of the urinary bladder could activate a significantly smaller number of Fos cells in the cord compared with noxious stimulation (Birder and de Groat, 1993). Our findings that nepadutant was not effective in reducing the Fos response to distension alone is consistent with the observation that nepadutant reduces the firing of spinal neurons to CRD after inflammation of the colon (Laird et al, 2001), whereas in the absence of colonic inflammation, treatment with nepadutant was ineffective in reducing the neuronal response to CRD.…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Effect of Nepadutant, a Neurokinin 2 Tachykinin Receptor Antagonist, on Immediate-Early Gene Expression after Trinitrobenzenesulfonic Acid-Induced Colitis in the Rat

Birder

Kiss²,

Groat³

et al. 2003

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Tachykinins have been implicated in inflammatory responses such as those occurring in inflammatory bowel disease. Accordingly, we investigated the effect of a selective neurokinin (NK) 2 receptor antagonist, nepadutant, on proto-oncogene expression in the L 6 -S 1 spinal cord as well as in dorsal root ganglion (DRG) neurons after either non-noxious colorectal distension (CRD) or trinitrobenzenesulfonic acid (TNBS)-induced colitis in the adult rat. In both preparations, c-fos was expressed in similar spinal cord regions, including medial and lateral dorsal horn, dorsal commissure (DCM; laminae X above the central canal), and the sacral parasympathetic nucleus (SPN, laminae V-VII). However, TNBS-induced colitis produced significantly larger numbers (8 -10-fold increase over control) of Fos-positive spinal cord neurons. In addition, there was also a significant increase (3-4-fold) in the number of Jun-positive colon DRG neurons after colitis compared with CRD. Nepadutant had no significant effect on proto-oncogene expression induced by CRD in either spinal cord neurons or DRG neurons. In contrast, nepadutant significantly decreased (70%) the number of Fos-positive neurons in dorsal horn, DCM, and SPN spinal cord regions and significantly decreased (75%) the number of Jun-positive DRG neurons after TNBS-induced irritation of the colon. These findings indicate that nepadutant suppresses the responses of colonic afferent neurons to nociceptive stimuli and that NK2 receptor antagonists may be beneficial in the treatment of sensory symptoms of colitis.Inflammatory bowel disease is often associated with increased painful sensations in response to colorectal disten-

show abstract

Section: Discussionsupporting

confidence: 93%

“…The effect of nepadutant is attributable to an action on peripheral NK2 receptors to decrease the responses to nociceptive stimuli because the drug does not penetrate the bloodbrain barrier (Catalioto et al, 1998;Laird et al, 2001). This is consistent with the effect of the drug to decrease Jun in DRG neurons.…”

Section: Discussionsupporting

confidence: 66%

Effect of Nepadutant, a Neurokinin 2 Tachykinin Receptor Antagonist, on Immediate-Early Gene Expression after Trinitrobenzenesulfonic Acid-Induced Colitis in the Rat

Birder

Kiss²,

Groat³

et al. 2003

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, intracolonic administration of zymosan to the rat produces hyperalgesia (10), sensitization of pelvic nerve colon afferents (11), and activation of silent fibers (18). Centrally, spinal N-methyl-D-aspartate (10,21,28,65), neurokinin (22,23,31), opioid (45) and CCK B receptors (15), and nitric oxide (9) have been shown to modulate behavioral or electrophysiological responses to noxious colon distension.…”

Section: Discussionmentioning

confidence: 99%

Quantitative assessment and characterization of visceral nociception and hyperalgesia in mice

Kamp

Jones

Tillman

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

101

108

View full text Add to dashboard Cite

Colorectal distension (CRD) is a well-characterized model of visceral nociception, which we adapted to the mouse. CRD reproducibly evoked contractions of the abdominal musculature [visceromotor response (VMR)], which was graded to stimulus intensity. The magnitude of VMR was greater in male C57BL6 and female 129S6 mice than in male 129S6 and B6.129 mice. In 129S6, C57BL6, and B6.129 mice strains, VMR was reduced dose dependently by morphine (1-10 mg/kg) and by the -opioid agonist U-69593 (0.2-2 mg/kg), although U-69593 was significantly less potent in C57BL6 mice. In additional experiments, the VMR was recorded from adult male 129S6 mice before and after intracolonic administration of various irritants. Only 30% ethanol significantly enhanced responses to CRD. The colon hyperalgesia persisted for 14 days and was associated with a significant shift of the morphine doseresponse function to the left. We believe this will be a useful model for study of visceral nociception and hyperalgesia, including studies of transgenic mice with mutations relevant to pain. colon; visceral pain; knockout mice; strain; gender; -opioid PAIN IS THE MOST COMMON REASON patients seek care from a physician, and the majority of visits are for pain of visceral origin. Current knowledge about mechanisms of pain has been derived from studies of somatic, principally cutaneous pain. Visceral pain has been less well studied, in part, because of more difficult access to visceral structures. Additionally, stimuli that are painful when applied to the skin, such as burning, crushing, and cutting, evoke no pain when applied to most visceral structures. Furthermore, there is growing evidence that the mechanisms of visceral and cutaneous pain are different (8,19). Certainly, the characteristics of these pains are different; visceral pain is diffuse, poorly localized, and referred to overlying structures (see Refs. 7 and 46 for reviews).Balloon distension of hollow organs, such as the colon, stomach, or urinary bladder produces pain in humans and quantifiable behavioral and autonomic responses in nonhuman animals. These responses have been most extensively characterized for colorectal distension (CRD) in the rat. When applied to rats at pressures comparable to those that produce pain in humans, CRD is aversive and produces tachycardia, pressor effects, contraction of the abdominal musculature, activation of afferent (sensory) fibers in the pelvic nerve, and activation of second-order neurons in the dorsal horn of the spinal cord (45,46,52).The availability of genetically modified mice has increased interest in the mouse as a nonhuman experimental animal. Numerous mice have been generated with mutations relevant to the study of pain; most have been tested in cutaneous models of nociception only. Some transgenic mice have been tested using the intraperitoneal acetic acid model of visceral nociception (writhing test); however, a limited understanding of the underlying structures and sensory neurons activated in this model confounds interpretation of resul...

show abstract

“…Administration of NK2 antagonists inhibits the enhanced responses of spinal neurons to colorectal distension after inflammation, but has no effect on spinal neuronal responses to pelvic nerve stimulation or on responses to distension of the normal colon, suggesting a peripheral mechanism of action selective for the inflamed colon (Laird et al, 2001b). Intrathecal administration of an NK2 receptor antagonist has no effect on the reflex responses to distension of the sensitized colon (Gaudreau and Plourde, 2003), further supporting the idea that the analgesic effects of NK2 receptor antagonists are restricted to the periphery.…”

Section: Tachykinins and Visceral Nociceptive Transmissionmentioning

confidence: 97%

Understanding the signaling and transmission of visceral nociceptive events

2004

Self Cite

View full text Add to dashboard Cite

Visceral pain can be considered as part of the defense reactions of the body against harmful stimuli, particularly of those that impinge on the mucosal lining of hollow organs. It is a problem of considerable clinical relevance, and its neurobiological mechanisms differ from those of somatic nociceptive or neuropathic pain. Much progress had been made in recent years in the understanding of the functional properties of the visceral nociceptors that trigger pain states, their molecular mechanisms of activation and sensitization and on their central actions. Some molecular targets have been identified as key players in the activation and sensitization of visceral nociceptors, notably ASICs, TTX-resistant Na channels and the TRPV1 receptor. Some nonneural elements of visceral organs, such as the urothelium have been shown to play active roles in the transduction of visceral sensory events by mechanisms involving ATP release by the urothelial cells. Certain well-known neurotransmitters, such as the tachykinin family of neuropeptides, likely play an important role in the peripheral and central activation of visceral nociceptive afferents and in the generation of visceral hyperalgesia. This article reviews current evidence on the mechanisms of activation and sensitization of visceral nociceptive afferents and on their role in the triggering and maintenance of clinically relevant visceral pain states.

show abstract

Responses of rat spinal neurons to distension of inflamed colon: role of tachykinin NK2 receptors

Cited by 44 publications

References 22 publications

Effect of Nepadutant, a Neurokinin 2 Tachykinin Receptor Antagonist, on Immediate-Early Gene Expression after Trinitrobenzenesulfonic Acid-Induced Colitis in the Rat

Effect of Nepadutant, a Neurokinin 2 Tachykinin Receptor Antagonist, on Immediate-Early Gene Expression after Trinitrobenzenesulfonic Acid-Induced Colitis in the Rat

Quantitative assessment and characterization of visceral nociception and hyperalgesia in mice

Understanding the signaling and transmission of visceral nociceptive events

Contact Info

Product

Resources

About