Role of neurokinin 3 receptors on responses to colorectal distention in the rat: Electrophysiological and behavioral studies

doi:10.1016/S0016-5085(99)70015-6

Gastroenterology

Volume 116, Issue 5, May 1999, Pages 1124-1131

https://doi.org/10.1016/S0016-5085(99)70015-6 Get rights and content

Abstract

Background & Aims: Tachykinins contribute to the control of gastrointestinal motility and modulation of somatic and visceral pain. The role of neurokinin (NK) B and NK3 receptors in visceral pain and gastrointestinal disorders has not been determined. Methods: Using electromyographic recordings of both abdominal and colonic muscle and electrophysiological recordings of pelvic nerve afferent fibers, we studied drug effects on responses to colorectal distention. Results: In awake rats, intraperitoneal administration of the NK3-receptor antagonist SR 142,801 reduced, whereas the NK3-receptor agonist senktide increased, both the rectocolonic inhibitory reflex and abdominal contractions produced by colorectal distention. In contrast, intracerebroventricular administration of SR 142,801 increased the number of abdominal contractions without affecting the rectocolonic inhibitory reflex produced by colorectal distention. In a similar manner, intracerebroventricular injection of senktide diminished the number of abdominal contractions. In electrophysiological experiments, SR 142,801 decreased responses of pelvic nerve afferent fibers to colorectal distention. Responses of pelvic nerve fibers to urinary bladder distention, however, were unaffected by SR 142,801. Conclusions: These results suggest that peripheral NK3 receptors are involved in the mediation of both visceral nociception and gastrointestinal disorders. Also, central NK3 receptors seem to play a role in the modulation of visceral nociception.

GASTROENTEROLOGY 1999;116:1124-1131

Section snippets

Materials and methods

The behavioral experiments were performed in Toulouse, France, and the electrophysiological experiments in Iowa City, Iowa. The experimental protocols were approved by the institutional animal care and use committees of the institutions.

Senktide

The NK3-receptor agonist senktide had no effect on resting colonic motility. In 8 rats, the mean number of spike bursts with the balloon in the colon (0-mL distention) was 7.4 ± 0.2 before and 7.7 ± 0.6 after perfusion of senktide (5 μg · kg⁻¹ · 30 min⁻¹). However, senktide significantly reduced the number of spike bursts recorded in the proximal colon in response to CRD, particularly at the greater volumes of distention (Figure 1A).

. Effect of IP infusion of senktide (5 μg · kg⁻¹ · 30 min⁻¹) on

Discussion

This study documents a role for NK3 receptors in viscerosensitivity. The results show that peripheral NK3 receptors are involved in both the rectocolonic inhibitory reflex and visceral nociception produced by CRD. Electrophysiological recordings of mechanosensitive afferent fibers in the pelvic nerve confirm the involvement of peripheral NK3 receptors in response to noxious CRD. This study also documents a role for central NK3 receptors in viscerosensitivity. The effects of central

Acknowledgements

The authors thank Dr. Mark Urban for providing critical comments on an earlier version of this report, Mike Burcham for production of the graphics, and Susan Birely for invaluable secretarial assistance.

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Yet NK2R antagonists reduced abdominal contractions induced by acetic acid (Julia & Bueno, 1997). Similarly, in acute visceral pain, an NK3R antagonists reduced both the number of abdominal contractions and responses of pelvic nerve afferents to noxious colonic distension (Julia, Su, Bueno, & Gebhart, 1999). Considering that NK2R are barely present in the adult human brain, these responses evidenced in animal models could be absent in human (Dietl & Palacios, 1991; Saffroy, Torrens, Glowinski, & Beaujouan, 2001).
Hybrid compounds (also known as chimeras, designed multiple ligands, bivalent compounds) are chemical units where two active components, usually possessing affinity and selectivity for distinct molecular targets, are combined as a single chemical entity. The rationale for using a chimeric approach is well documented as such novel drugs are characterized by their enhanced enzymatic stability and biological activity. This allows their use at lower concentrations, increasing their safety profile, particularly when considering undesirable side effects.
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Rats were placed in polypropylene tunnels (diameter 7 cm, length 20 cm), where they could not move, escape or turn around. Rats were accustomed to this procedure for 3 days before any CRD, in order to achieve familiarization with that environment [25]. The balloon used for CRD was 4 cm long and made from a latex condom.
Nociceptin/orphanin FQ (N/OFQ) and its NOP receptors are present in the central nervous system and in the periphery playing important roles in the modulation of gastrointestinal functions and pain. The aim of this study was to investigate the role of central and peripheral N/OFQ–NOP receptor system in the nociceptive response to colorectal distension (CRD) in basal condition and in two models of gut hypersensitivity triggered by both inflammation and stress. Male Wistar rats were tested in basal and in post-inflammatory conditions, i.e., 5 days after IC TNBS instillation (80 mg/Kg) and received N/OFQ (2 nmol/Kg IP), UFP-101 (a selective NOP receptor antagonist, 10 nmol/Kg IP), N/OFQ+UFP-101, N/OFQ (0.5 nmol/rat ICV) or vehicle. Female rats were tested in basal and after partial restraint stress receiving the same pharmacological treatment. CRD was performed using barostat and abdominal contractions were recorded by electromyography. In basal condition, N/OFQ, ICV and IP injected, did not modify basal visceral sensitivity. Both in TNBS and stress-induced hyperalgesia, IP but not ICV injection of N/OFQ significantly decreased the number of abdominal contractions. Peripheral injection of UFP-101 antagonized N/OFQ effect. Moreover, in post-inflammatory colitis, UFP-101, injected alone, exacerbated visceral hyperalgesia to CRD compared with vehicle. These findings indicate that in rats, N/OFQ, only peripherally injected, reduces visceral hypersensitivity triggered by inflammation or stress without affecting basal sensitivity. N/OFQ visceral anti-hyperalgesic effect involves peripheral NOP receptors. In a post-inflammatory, but not in an acute stress colitis model, N/OFQergic system is endogenously activated.
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Citation Excerpt :
In addition, Laird and coworkers [191] have shown that intracolonic instillation of acetic acid or capsaicin fails to produce either acute (cardiovascular) responses or primary hyperalgesia. Also the NK3 receptor (located at peripheral or/and central level) could play a role in visceral hyperalgesia, due to the reported effectiveness of either intraperitoneal [245] or intrathecal [246] administration of SR 142801 (a tachykinin NK3 receptor-selective antagonist) in reducing reflex abdominal contractions elicited by various nociceptive stimuli. Although the precise site at which endogenous tachykinins act to mediate visceral pain is still matter of debate [247], tachykinin receptor antagonists have been proposed for the treatment of functional gastrointestinal disorders characterized by visceral pain such as irritable bowel syndrome [248,249] (Table 4).
Tachykinin-containing projections of capsaicin-sensitive primary afferent neurons widely distribute to visceral organs of the respiratory, gastrointestinal, and genitourinary systems. At this level, tachykinins, along with calcitonin gene-related peptide and other neuropeptides, can be released by adequate stimuli having pathological rather than physiological relevance. Such stimuli may represent chemical irritants to the respiratory tree or alimentary tract, or noxious agents secreted into the urinary system. Tachykinins produced in the visceral organs are part of the responses obtained at somatic level by antidromic activation of capsaicin-sensitive nerve terminals and collectively known as “neurogenic inflammation”: that is, increase in vascular permeability and plasma protein leakage followed by edema. In addition, tachykinins produced at visceral level elicit smooth muscle contraction, neuronal stimulation, mucus secretion, and recruitment/activation of immune cells. The physiological significance of these effects is that to afford protection toward chemical irritants or noxious stimuli by facilitating their removal from the body. Nonetheless, a large body of preclinical evidence exists indicating that tachykinins participate to the genesis and/or maintenance of symptoms accompanying various human diseases, such as asthma/bronchial hyperreactivity, cystitis of various etiologies, inflammatory bowel diseases, and irritable bowel syndrome. Tachykinin receptor antagonists, which are proved to prevent/reduce tachykinin-mediated effects in experimental animal models of these pathologies, are expected to afford therapeutically relevant effects in humans.
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^☆: Address requests for reprints to: G. F. Gebhart, Ph.D., Department of Pharmacology, Bowen Science Building, University of Iowa, Iowa City, Iowa 52242. e-mail: [email protected]; fax: (319) 335-8930.

^☆☆: Supported by National Institutes of Health grant NS 19912.

^★: Dr. Julia's current address is: Institut de recherche Jouveinal/Parke-Davis, 3-9 rue de la Loge, BP 100, 94265 Fresnes Cedex, France.

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Alimentary TractRole of neurokinin 3 receptors on responses to colorectal distention in the rat: Electrophysiological and behavioral studies☆,☆☆,★

Abstract

Section snippets

Materials and methods

Senktide

Discussion

Acknowledgements

Brain Res

Biochem Biophys Res Commun

Gastroenterology

Gastroenterology

Regul Pept

Life Sci

Regul Pep

Neuropep-tides

Neuropep-tides

Neuroscience

Neuroscience

Life Sci

Brain Res

Neurosci Res

Brain Res

Peptides

Neuroscience

Experimental colitis alters visceromotor response to colorectal distension in awake rats

Dig Dis Sci

Endorphins mediate overshoot of substance P–induced facilation of a spinal nociceptive reflex

Can J Pharmacol

Neurotransmitter functions of mammalian tachykinins

Physiol Rev

Alimentary Tract
Role of neurokinin 3 receptors on responses to colorectal distention in the rat: Electrophysiological and behavioral studies☆,☆☆,★