Involvement of the neurotensin receptor 1 in the behavioral effects of two neurotensin agonists, NT-2 and NT69L: Lack of hypothermic, antinociceptive and antipsychotic actions in receptor knockout mice

Mechanic, Jordan; Sutton, Janette; Berson, Amy E.; Wu, Xingkun; Kwan, Joyce; Schreiber, Rudy; Pang, Zhen; Button, Donald

doi:10.1016/j.euroneuro.2009.01.004

Cited by 33 publications

(37 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results demonstrate for the first time in a persistent pain model that the spontaneous nociceptive behaviors, analyzed either by the weighted-scores method or rated by monitoring the total time spent in flinching/licking/biting were equivalent in NTS1-KO male mice and their wild-type littermates. These results are consistent with previous findings showing similar hot-plate reaction times or tail-flick response latencies between NTS1-deficient and wild-type mice (Pettibone et al, 2002, Maeno et al, 2004, Mechanic et al, 2009. Interestingly, we recently demonstrated that baseline pain thresholds of NTS2-KO mice were also not different from wild-type mice after the application of thermal or chemical stimuli (Lafrance et al, 2010).…”

Section: Discussionsupporting

confidence: 82%

“…Studies in NTS1 knockout mouse derived from different genetic background also pointed to the NTS1 subtype as a NT antinociceptor. Indeed, NTS1-deficient mice failed to exhibit analgesic responses to thermal stimuli following central injection of NT or systemic delivery of brain penetrating NT analogs (NT-1, NT-2 and NT69L) (Pettibone et al, 2002, Mechanic et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Altered morphine-induced analgesia in neurotensin type 1 receptor null mice

et al. 2010

View full text Add to dashboard Cite

Both neurotensin (NT) and opioid agonists have been shown to induce antinociception in rodents after central administration. Besides, previous studies have revealed the existence of functional interactions between NT and opioid systems in the regulation of pain processing. We recently demonstrated that NTS1 receptors play a key role in the mediation of the analgesic effects of NT in long-lasting pain. In the present study, we therefore investigated whether NTS1 gene deletion affected the antinociceptive action of mu opioid drugs. To this end, pain behavioral responses to formalin were determined following systemic administration of morphine in both male and female NTS1 knockout mice. Acute injection of morphine (2 or 5 mg/kg) produced strong antinociceptive effects in both male and female wild-type littermates, with no significant sex differences. On the other hand, morphine analgesia was considerably reduced in NTS1-deficient mice of both sexes compared to their respective controls, indicating that the NTS1 receptor actively participates in mu opioid alleviating pain. By examining specifically the flinching, licking and biting nociceptive behaviors, we also showed that the functional crosstalk between NTS1 and mu opioid receptors influences the supraspinally-mediated behaviors. Interestingly, sexual dimorphic action of morphine-induced pain inhibition was found in NTS1 null mice in the formalin test, suggesting that the endogenous NT system interacts differently with the opioid network in male and female mice. Altogether, these results demonstrated that NTS1 receptor activation operates downstream to the opioidergic transmission and that NTS1-selective agonists combined with morphine may act synergistically to reduce persistent pain.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Altered morphine-induced analgesia in neurotensin type 1 receptor null mice

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Our group has demonstrated that acute and delayed administrations of HPI-201 and HPI-363 show marked protective effects against brain injury after ischemic and hemorrhagic strokes as well as traumatic brain injury (TBI) in adult and neonatal rodent models (Choi et al, 2012; Lee et al, 2014; Lee et al, 2016b; Wei et al, 2013). NRT1 agonists additionally show antinociceptive and antipsychotic actions (Guillemette et al, 2012; Mechanic et al, 2009). We have identified that the cooling action of the NRT1 compounds, but not their other pharmacological effects, is responsible for observed neuroprotection because when the body temperature is forced to stay at normal level after the drug administration its neuroprotective effect is eliminated (Choi et al, 2012; Gu et al, 2015; Lee et al, 2014; Wei et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice

Lee

Wei

Cao

et al. 2016

Neurobiology of Disease

121

View full text Add to dashboard Cite

Stroke is a leading threat to human life and health in the US and around the globe, while very few effective treatments are available for stroke patients. Preclinical and clinical studies have shown that therapeutic hypothermia (TH) is a potential treatment for stroke. Using novel neurotensin receptor 1 (NTR1) agonists, we have demonstrated pharmacologically induced hypothermia and protective effects against brain damages after ischemic stroke, hemorrhage stroke, and traumatic brain injury (TBI) in rodent models. To further characterize the mechanism of TH-induced brain protection, we examined the effect of TH (at ±33°C for 6 hrs) induced by the NTR1 agonist HPI-201 or physical (ice/cold air) cooling on inflammatory responses after ischemic stroke in mice and oxygen glucose deprivation (OGD) in cortical neuronal cultures. Seven days after focal cortical ischemia, microglia activation in the penumbra reached a peak level, which was significantly attenuated by TH treatments commenced 30 min after stroke. The TH treatment decreased the expression of M1 type reactive factors including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-12, IL-23, and inducible nitric oxide synthase (iNOS) measured by RT-PCR and Western blot analyses. Meanwhile, TH treatments increased the expression of M2 type reactive factors including IL-10, Fizz1, Ym1, and arginase-1. In the ischemic brain and in cortical neuronal/BV2 microglia cultures subjected to OGD, TH attenuated the expression of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), two key chemokines in the regulation of microglia activation and infiltration. Consistently, physical cooling during OGD significantly decreased microglia migration 16 hrs after OGD. Finally, TH improved functional recovery at 1, 3, and 7 days after stroke. This study reveals the first evidence for hypothermia mediated regulation on inflammatory factor expression, microglia polarization, migration and indicates that the anti-inflammatory effect is an important mechanism underlying the brain protective effects of a TH therapy.

show abstract

“…The high affinity NTSR1, insensitive to levocabastine, is involved in a series of actions of NT including the antipsychotic like behavior (Mechanic et al, 2009), the inhibition of weak fear memory (Yamada et al, 2010) and the nociceptive signaling in a rat formalin tonic pain model (Roussy et al, 2008). The deletion in mice of the low affinity NTSR2, sensitive to levocabastine, results in the loss of thermal (Maeno et al, 2004) and tonic nociception of NT (Roussy et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Increased Brain Neurotensin and NTSR2 Lead to Weak Nociception in NTSR3/Sortilin Knockout Mice

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

Involvement of the neurotensin receptor 1 in the behavioral effects of two neurotensin agonists, NT-2 and NT69L: Lack of hypothermic, antinociceptive and antipsychotic actions in receptor knockout mice

Cited by 33 publications

References 24 publications

Altered morphine-induced analgesia in neurotensin type 1 receptor null mice

Altered morphine-induced analgesia in neurotensin type 1 receptor null mice

Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice

Increased Brain Neurotensin and NTSR2 Lead to Weak Nociception in NTSR3/Sortilin Knockout Mice

Contact Info

Product

Resources

About