Abstract
The neuropeptide neurotensin (NT) elicits numerous pharmacological effects through three different receptors (NTSR1, NTSR2, and NTSR3 also called sortilin). Pharmacological approaches and generation of NTSR1 and NTSR2-deficient mice allowed to determine the NT-induced antipsychotic like behavior, the inhibitory of weak fear memory and the nociceptive signaling in a rat formalin tonic pain model to NTSR1. Conversely, the effects of NT on thermal and tonic nociceptions were mediated by NTSR2. However, the role of NTSR3/sortilin on the neurotensinergic system was not investigated. Here, by using C57Bl/6J mouse model in which the gene coding for NTSR3/sortilin has been inactivated, we observed a modification of the expression of both NTSR2 and NT itself. Quantitative PCR and protein expression using Western blot analyses and AlphaLisa™ technology resulted in the observation that brain NTSR2 as well as brain and blood NT were 2-fold increased in KO mice leading to a resistance of these mice to thermal and chemical pain. These data confirm that NTSR3/sortilin interacts with other NT receptors (i.e., NTSR2) and that its deletion modifies also the affinity of this receptor to NT.
Highlights
The endogenous neuropeptide NT is involved in numerous biological functions both in the brain and in periphery organs
In order to quantify the amount of NT binding sites corresponding to NTSR1 and NTSR2 in the brain of wild type (WT) and NTSR3/sortilin deficient mice (KO-NTSR3), we first performed saturation binding experiments of iodinated NT on homogenates prepared from the indicated brains in the absence or in the presence of the NTSR2 selective blocker levocabastine (1 μM) (Kitabgi et al, 1987)
We provide evidence that the absence of NTSR3/sortilin leads to modificiation of the neurotensinergic system with the consequence that these mice are less sensitive to pain as clearly shown by the two different tests (Figure 4)
Summary
The endogenous neuropeptide NT is involved in numerous biological functions both in the brain and in periphery organs (for review see Kleczkowska and Lipkowski, 2013). These processes include dopamine transmission (Kitabgi et al, 1989), analgesia (Dobner, 2006), hypothermia (Popp et al, 2007) and hormonal activity regulation (Rostene and Alexander, 1997; Beraud-Dufour et al, 2010). Levocabastine is a well characterized compound able to selectively bind by competition with NT to the low affinity NT receptor (i.e., NTSR2) without affecting the binding of NT to NTSR1 in murine brain (Kitabgi et al, 1987; Mazella et al, 1998)
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