Endogenous neurotensin facilitates visceral nociception and is required for stress-induced antinociception in mice and rats

doi:10.1016/j.neuroscience.2004.04.034

Neuroscience

Volume 126, Issue 4, 2004, Pages 1023-1032

https://doi.org/10.1016/j.neuroscience.2004.04.034 Get rights and content

Abstract

Central neurotensin (NT) administration can both facilitate and inhibit somatic and visceral nociception, depending on the dose and administration site. NT microinjection in the rostroventral medulla facilitates nociception at low doses, while NT antagonist microinjection can markedly attenuate nociception, supporting the hypothesis that endogenous NT facilitates nociception. However, higher doses of NT produce a μ-opioid receptor-independent analgesia, similar to that resulting from various intense stressors. Furthermore, intense stress results in increased NT expression in several hypothalamic nuclei that have been implicated in stress-induced antinociception (SIAN); however, there is little direct evidence that endogenous NT is required for SIAN. We have investigated the role of endogenous NT in both basal visceral nociception and SIAN using both NT knockout mice and pharmacological approaches in rats. Visceral nociception was monitored by measuring visceromotor responses during colorectal distension both prior to and following water avoidance stress. Visceral nociception was significantly attenuated in both NT knockout mice and rats pre-treated with the NT antagonist SR 48692. Disruption of NT signaling also blocked SIAN, revealing a novel stress-induced hyperalgesic response that was significantly greater in female than in male rats. NT was also required for acetic acid-induced hyperalgesia. These results indicate that endogenous NT normally facilitates visceral pain responses, is required for irritant-induced hyperalgesia, and plays a critical role in SIAN.

Section snippets

Animals

Animal protocols were approved by the University of Massachusetts Medical School Institutional Animal Care and Use Committee and were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 80-23, revised 1996). Every effort was made to minimize the number of animals used and their suffering.

Mice

Female NT knockout and wild type mice (18–25 g) were generated as described using heterozygous mating pairs after backcrossing

NT signaling facilitates visceral nociception

To examine whether NT signaling is important for nociception during CRD, both NT knockout and wild type mice were subjected to CRD and VMRs were measured (Fig. 1A). The NT/neuromedin N gene is disrupted in the NT knockout mouse line used here and these mice do not express detectable levels of NT or preproneurotensin/neuromedin N mRNA in the either the brain or the gastrointestinal tract (Dobner et al., 2001). The abdominal VMRs to each volume of CRD were significantly lower in NT knockout mice

Discussion

We have used both genetic and pharmacological approaches to demonstrate that NT (and/or neuromedin N) signaling is required for both normal visceral nociception and SIAN in rodents. Visceral pain responses were significantly attenuated in both NT knockout mice and rats pre-treated with the NT antagonist SR 48692, indicating that endogenous NT signaling is required for normal visceral nociception. The disruption of NT signaling had an even more dramatic effect on SIAN, reversing the effect of

Acknowledgements

This work was supported by National Institutes of Health grants DK28565 (R.E.C.) and DK99004 (R.E.C.), a grant from the University of Massachusetts Medical School Genetics Program (P.R.D.), and a Pilot and Feasibility grant from the University of Massachusetts Medical School Diabetes and Endocrinology Research Center 5P30 DK32520 (P.R.D.).

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The role of NT has been shown in stress-induced analgesia, as well (Gui et al., 2004). However, in the absence of stress NTergic transmission facilitates visceral nociception: NT knockout mice showed an attenuated visceral nociception and i.p. injection of NT antagonist SR 48692 decreased nociception (Gui et al., 2004). NT is involved in the regulation of anxiety.
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Moreover, both orexin and substance P were released after LH activation, so it will be interesting to examine if there are interactions between these two neuropeptide systems during SIA. Similarly, neurotensin was also suggested to be involved in SIA.159 It will also be interesting to see if neurotensin plays a role in endocannabinoid-mediated SIA.
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Although many studies clearly indicate the predominant involvement of NTS2 receptor (Gully et al., 1995; Dubuc et al., 1999), the NTS1 receptor subtype signaling is required for at least some aspects of NT-induced analgesia (Gui et al., 2004). Gui et al. (2004) as an example of this fact indicates studies in which NTS1 knockout mice displayed defects in NT-induced analgesia in the hot plate test. Additionally, NT analog NT69L has been reported to cause a rapid and persistent antinociceptive effect as determined by the hot plate test (St-Gelais et al., 2006).
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¹: Present address: Department of Pathology, University of Illinois at Chicago College of Medicine, 1819 West Polk St, Chicago, IL 60612, USA.

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Endogenous neurotensin facilitates visceral nociception and is required for stress-induced antinociception in mice and rats

Abstract

Section snippets

Animals

Mice

NT signaling facilitates visceral nociception

Discussion

Acknowledgements

Brain Res

Brain Res

Brain Res

Pharmacol Biochem Behav

Eur J Pharmacol

Eur J Pharmacol

Physiol Behav

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Physiol Behav

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Physiol Behav

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