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

Birder, Lori A.; Kiss, Susanna; Groat, William C. de; Lecci, Alessandro; Maggi, Carlo Alberto

doi:10.1124/jpet.102.042077

Cited by 20 publications

(14 citation statements)

References 34 publications

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“…For the same reasons, many compounds designed for human neurokinin receptors failed to exhibit any analgesic effect in animal studies. Regardless, several animal studies have documented that selective antagonists for all three receptors (NK1, NK2, and NK3) attenuate visceral pain in several animal species, including mice, rats, rabbits, guinea pigs and gerbils (Gardeau and Plourde 2003; Julia et al 1994, 1999; Laird et al 2001a, b; Kamp et al 2001; Fioramonti et al 2003; Birder et al 2003; Greenwood-van Meerveld et al 2003; Bradesi et al 2003; Okano et al 2002; Kakol-Palm et al 2008). Although in many of these studies, the sites of action of the antagonists were not well characterized, presumably most of the antagonists modulate spinal processing by blocking presynaptic and/or postsynaptic neurokinin receptors in the spinal cord.…”

Section: Contribution Of Sensory Afferents In Visceral Painmentioning

confidence: 99%

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Visceral Pain: The Neurophysiological Mechanism

Sengupta

2009

Handbook of Experimental Pharmacology

164

115

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The mechanism of visceral pain is still less understood compared with that of somatic pain. This is primarily due to the diverse nature of visceral pain compounded by multiple factors such as sexual dimorphism, psychological stress, genetic trait, and the nature of predisposed disease. Due to multiple contributing factors there is an enormous challenge to develop animal models that ideally mimic the exact disease condition. In spite of that, it is well recognized that visceral hypersensitivity can occur due to (1) sensitization of primary sensory afferents innervating the viscera, (2) hyperexcitability of spinal ascending neurons (central sensitization) receiving synaptic input from the viscera, and (3) dysregulation of descending pathways that modulate spinal nociceptive transmission. Depending on the type of stimulus condition, different neural pathways are involved in chronic pain. In early-life psychological stress such as maternal separation, chronic pain occurs later in life due to dysregulation of the hypothalamic–pituitary–adrenal axis and significant increase in corticotrophin releasing factor (CRF) secretion. In contrast, in early-life inflammatory conditions such as colitis and cystitis, there is dysregulation of the descending opioidergic system that results excessive pain perception (i.e., visceral hyperalgesia). Functional bowel disorders and chronic pelvic pain represent unexplained pain that is not associated with identifiable organic diseases. Often pain overlaps between two organs and approximately 35% of patients with chronic pelvic pain showed significant improvement when treated for functional bowel disorders. Animal studies have documented that two main components such as (1) dichotomy of primary afferent fibers innervating two pelvic organs and (2) common convergence of two afferent fibers onto a spinal dorsal horn are contributing factors for organ-to-organ pain overlap. With reports emerging about the varieties of peptide molecules involved in the pathological conditions of visceral pain, it is expected that better therapy will be achieved relatively soon to manage chronic visceral pain.

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Section: Contribution Of Sensory Afferents In Visceral Painmentioning

confidence: 99%

“…Similarly, there are a few reports of the evaluation of the peripheral effects of these drugs. Two reports have documented the inhibitory effects of NK2 and NK3 receptor antagonists on colonic PN afferents (Julia et al 1999; Birder et al 2003). …”

Section: Contribution Of Sensory Afferents In Visceral Painmentioning

confidence: 99%

Visceral Pain: The Neurophysiological Mechanism

Sengupta

2009

Handbook of Experimental Pharmacology

164

115

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“…(16) Immediateearly genes (such as c-fos) have been reported to be elevated in the lumbosacral spinal cord and DRG following bladder and colon irritation. (17)(18)(19) NGF, a potent mediator of hyperalgesia associated with inflammation, is upregulated in response to LPS in a mouse cystitis model. (20) We also examined changes in MIF and COX-2 in the prostate in a preliminary attempt to study the possible role of MIF in viscerovisceral interactions.…”

Section: Introduction B Ladder Inflammation Is Associated With Urinarmentioning

confidence: 99%

Macrophage Migration Inhibitory Factor Is Upregulated in an Endotoxin-Induced Model of Bladder Inflammation in Rats

Meyer-Siegler

Ordorica²,

Vera³

2004

Journal of Interferon & Cytokine Research

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Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine found in epithelial cells as preformed stores, such that MIF release can activate innate immune responses. Our identification of MIF stores in the urothelium suggests that MIF may function in the bladder's initial response to infectious stimuli, such as lipopolysaccharide (LPS). To test this hypothesis, we observed changes in MIF, cyclooxygenase-2 (COX-2) and c-fos in the bladder, L6-S1 spinal cord, dorsal root ganglion (DRG), and major pelvic ganglion (MPG) and MIF changes in the prostate following intravesical LPS. Intravesical LPS induced bladder edema and leukocyte infiltration, as well as increased MIF protein and mRNA in the bladder and lumbosacral spinal cord. Expression of immediate-early gene c-fos, a transcription factor used as a marker of neuronal activation, increased in the L6-S1 spinal cord and L6-S1 DRG of rats that received LPS. We conclude that significant increases in bladder MIF expression and protein in response to intravesical LPS may represent part of this organ's initial innate immune response. In addition, MIF upregulation may represent a neural response to visceral inflammation. Finally, changes in prostate MIF content after intravesical LPS suggest that MIF may be involved in viscerovisceral interactions associated with chronic pelvic pain syndromes.

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“…However the increase in myenteric and mucosal tachykinins substance P (SP) and neuropeptide K (NPK) persisted for at least 14 weeks as did the increase in circular muscle thickness. These studies suggested that mucosal tachykinins and galanin might be good mucosal markers of both previous postinflammatory neural damage and persistent increase in myenteric tachykinins, which might in turn relate to visceral hypersensitivity as recent animal studies have suggested 16–18 …”

Section: Introductionmentioning

confidence: 99%

Post inflammatory damage to the enteric nervous system in diverticular disease and its relationship to symptoms

Simpson

Sundler

Humes

et al. 2009

Neurogastroenterology Motil

116

108

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Some patients with colonic diverticula suffer recurrent abdominal pain and exhibit visceral hypersensitivity, though the mechanism is unclear. Prior diverticulitis increases the risk of being symptomatic while experimental colitis in animals increases expression of neuropeptides within the enteric nervous system (ENS) which may mediate visceral hypersensitivity. Our aim was to determine the expression of neuropeptides within the ENS in diverticulitis (study 1) and in patients with symptomatic disease (study 2). Study 1 - Nerves in colonic resection specimens with either acute diverticulitis (AD, n = 16) or chronic diverticulitis (CD, n = 16) were assessed for neuropeptide expression recording % area staining with protein gene product (PGP9.5), substance P (SP), neuropeptide K (NPK), pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP) and galanin. Study 2 - Seventeen symptomatic and 15 asymptomatic patients with colonic diverticula underwent flexible sigmoidoscopy and multiple peridiverticular mucosal biopsies. Study 1- Neural tissue, as assessed by PGP staining was increased to a similar degree in circular muscle in both AD and CD. The CD specimens showed significant increases in the immunoreactivity of SP, NPK and galanin in both mucosal and circular muscle layer compared with controls. Study 2 - Mucosal histology was normal and PGP9.5 staining was similar between groups however patients with symptomatic diverticular disease demonstrated significantly higher levels of SP, NPK, VIP, PACAP and galanin within the mucosal plexus. Patients with symptomatic diverticular disease exhibit increased neuropeptides in mucosal biopsies which may reflect resolved prior inflammation, as it parallels the changes seen in acute and chronic diverticulitis.

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

Cited by 20 publications

References 34 publications

Visceral Pain: The Neurophysiological Mechanism

Visceral Pain: The Neurophysiological Mechanism

Macrophage Migration Inhibitory Factor Is Upregulated in an Endotoxin-Induced Model of Bladder Inflammation in Rats

Post inflammatory damage to the enteric nervous system in diverticular disease and its relationship to symptoms

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