Potent Spinal Analgesia Elicited through Stimulation of NTS2 Neurotensin Receptors

Sarret, Philippe; Esdaile, M. James; Perron, Amélie; Martinez, Jean; Stroh, Thomas; Beaudet, Alain

doi:10.1523/jneurosci.0810-05.2005

Cited by 69 publications

(93 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…NT does not induce analgesia because of its poor BBB penetration. As previously reported (40), NT increased the nociceptive threshold in the tailflick test ( Figure 5A). Likewise, i.t.…”

Section: In Vivo Brain Penetration and Plasma Stability Of Ang2002supporting

confidence: 90%

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Demeule¹,

Beaudet²,

Régina³

et al. 2014

J. Clin. Invest.

101

View full text Add to dashboard Cite

Neurotensin (NT) has emerged as an important modulator of nociceptive transmission and exerts its biological effects through interactions with 2 distinct GPCRs, NTS1 and NTS2. NT provides strong analgesia when administered directly into the brain; however, the blood-brain barrier (BBB) is a major obstacle for effective delivery of potential analgesics to the brain. To overcome this challenge, we synthesized chemical conjugates that are transported across the BBB via receptor-mediated transcytosis using the brain-penetrant peptide Angiopep-2 (An2), which targets LDL receptor-related protein-1 (LRP1). Using in situ brain perfusion in mice, we found that the compound ANG2002, a conjugate of An2 and NT, was transported at least 10 times more efficiently across the BBB than native NT. In vitro, ANG2002 bound NTS1 and NTS2 receptors and maintained NT-associated biological activity. In rats, i.v. ANG2002 induced a dose-dependent analgesia in the formalin model of persistent pain. At a dose of 0.05 mg/kg, ANG2002 effectively reversed pain behaviors induced by the development of neuropathic and bone cancer pain in animal models. The analgesic properties of ANG2002 demonstrated in this study suggest that this compound is effective for clinical management of persistent and chronic pain and establish the benefits of this technology for the development of neurotherapeutics.

show abstract

“…NT does not induce analgesia because of its poor BBB penetration. As previously reported (40), NT increased the nociceptive threshold in the tailflick test ( Figure 5A). Likewise, i.t.…”

Section: In Vivo Brain Penetration and Plasma Stability Of Ang2002supporting

confidence: 90%

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Demeule¹,

Beaudet²,

Régina³

et al. 2014

J. Clin. Invest.

101

View full text Add to dashboard Cite

show abstract

“…Inward currents in response to NT were also found in guineapig dorsal root ganglia (Kawarada et al, 2000). In situ hybridization revealed expression of NTR1 mainly in small sensory neurons of rat dorsal root ganglia (Zhang et al, 1995), and immunofluorescence analysis revealed the expression of NTR2 in both small and large cells (Sarret et al, 2005). We also confirmed by immunohistochemistry NTR1 expression in sensory ganglion cells, and nuclear NTR1 location supports internalization, also in this structure.…”

Section: Discussionsupporting

confidence: 73%

Neurotensin receptor 1 immunoreactivity in the peripheral ganglia and carotid body

Porzionato¹,

Macchi²,

Amagliani³

et al. 2009

Eur J Histochem

View full text Add to dashboard Cite

In the present study we investigated, through immunohistochemistry, the presence and location of neurotensin receptor 1 (NTR1) in the peripheral ganglia and carotid body of 16 humans and 5 rats. In both humans and rats, NTR1 immunostained ganglion cells were found in superior cervical ganglia (57.4±11.6% and 72.4±11.4%, respectively, p<0.05), enteric ganglia (51.9±10.4% and 64.6±6.1%, p<0.05), sensory ganglia (69.2±10.7% and 73.0±13.1%, p>0.05) and parasympathetic ganglia (52.1±14.1% and 59.4±14.0%, p>0.05), supporting a modulatory role for NT in these ganglia. Positivity was also detected in 45.6±9.2% and 50.8±6.8% of human and rat type I glomic cells, respectively, whereas type II cells were negative. Our findings suggest that NT produced by type I cells acts in an autocrine or paracrine way on the same cell type, playing a modulatory role on chemoception.

show abstract

“…In the brain, NT modulates dopaminergic transmission in the nigrostriatal and mesocortilimbic pathways as well as hormone secretion from the anterior pituitary (Vincent et al 1999). It also exerts potent hypothermic and analgesic effects (Sarret et al 2005). In the periphery, NT is synthesized and secreted by endocrine-like N cells predominantly in the small intestine (Reinecke 1985).…”

Section: Introductionmentioning

confidence: 99%

Immunocytochemical identification of low-affinity NTS2 neurotensin receptors in parietal cells of human gastric mucosa

Schulz¹,

Röcken²,

Ebert³

et al. 2006

Journal of Endocrinology

View full text Add to dashboard Cite

The biological effects of neurotensin (NT) are mediated by two distinct G protein-coupled receptors, NTS 1 and NTS 2 . Although it is well established that neurotensin inhibits gastric acid secretion in man, the plasma membrane receptor mediating these effects has not been visualized yet. We developed and characterized a novel antipeptide antibody to the carboxy-terminal region of the human NTS 2 receptor. The cellular and subcellular distribution of NTS 2 receptors was evaluated in various human gastrointestinal tissues. Specificity of the antiserum was demonstrated by (1) detection of a broadband migrating at M r 90 000-100 000 in Western blots of membranes from NTS 2 -expressing tissues; (2) cell-surface staining of NTS 2 -transfected cells; (3) translocation of NTS 2 receptor immunostaining after agonist exposure; and (4) abolition of tissue immunostaining by preadsorbtion of the antibody with its immunizing peptide. In the gastrointestinal tract, NTS 2 receptor immunoreactivity was highly abundant in parietal cells of the gastric mucosa, in neuroendocrine cells of the stomach small and large intestine, and in cells of the exocrine pancreas. NTS 2 receptors were clearly located in the plasma membrane and uniformly present on nearly all target cells. The presence of NTS 2 receptors was rarely detected in human tumors. This is the first localization of NTS 2 receptors in human formalin-fixed, paraffin-embedded tissues at the cellular level. The abundant expression of low-affinity NTS 2 receptors on the plasma membrane of human parietal cells provides a morphological substrate for the direct inhibition of gastric acid secretion observed after i.v. administration of neurotensin.

show abstract

Potent Spinal Analgesia Elicited through Stimulation of NTS2 Neurotensin Receptors

Cited by 69 publications

References 55 publications

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Neurotensin receptor 1 immunoreactivity in the peripheral ganglia and carotid body

Immunocytochemical identification of low-affinity NTS2 neurotensin receptors in parietal cells of human gastric mucosa

Contact Info

Product

Resources

About