Structure-antinociceptive activity of neurotensin and some novel analogues in the periaqueductal gray region of the brainstem

Al-Rodhan, Nayef R. F.; Richelson, Elliott; Gilbert, Judith A; McCormick, Daniel J.; Kanba, Kiyoko S.; Pfenning, Michael; Nelson, Al; Larson, Eric W.; Yaksh, Tony L.

doi:10.1016/0006-8993(91)90139-m

Cited by 77 publications

(36 citation statements)

References 39 publications

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“…In recent years, the NT tridecapeptide, which exerts biological effects by interacting with 2 distinct GPCRs (termed NTS1 and NTS2), has emerged as an important modulator of nociceptive transmission (22)(23)(24)(25). Existing data also indicate that the analgesic effects of NT are independent of the endogenous opioid system (26)(27)(28)(29)(30), and may act synergistically with opioids to reduce pain (31)(32)(33). In the present study, we investigated whether a novel An2-NT conjugate, ANG2002, can access brain parenchyma after systemic administration while retaining the analgesic properties To date, despite substantial investigation, little progress has been made in developing new, effective, and safe analgesics (19).…”

Section: Introductionmentioning

confidence: 97%

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

Demeule¹,

Beaudet²,

Régina³

et al. 2014

J. Clin. Invest.

101

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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.

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Section: Introductionmentioning

confidence: 97%

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

Demeule¹,

Beaudet²,

Régina³

et al. 2014

J. Clin. Invest.

101

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“…Pharmacological studies have indicated that, in the rat, centrally administered NT exerts antinociceptive actions both spinally and supraspinally. These antinociceptive effects are naloxone insensitive, implying that they are not dependent on endogenous opioid mechanisms (Clineschmidt et al, 1979;Nemeroff et al, 1979;Osbahr et al, 1981;Behbehani and Pert, 1984;al-Rodhan et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Potent Spinal Analgesia Elicited through Stimulation of NTS2 Neurotensin Receptors

Sarret¹,

Esdaile²,

Perron³

et al. 2005

J. Neurosci.

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Intrathecal administration of the neuropeptide neurotensin (NT) was shown previously to exert antinociceptive effects in a variety of acute spinal pain paradigms including hotplate, tail-flick, and writhing tests. In the present study, we sought to determine whether some of these antinociceptive effects might be elicited via stimulation of low-affinity NTS2 receptors. We first established, using immunoblotting and immunohistochemical techniques, that NTS2 receptors were extensively associated with putative spinal nociceptive pathways, both at the level of the dorsal root ganglia and of the superficial layers of the dorsal horn of the spinal cord. We then examined the effects of intrathecal administration of NT or selective NTS2 agonists on acute thermal pain. Both NT and NTS2 agonists, levocabastine and Boc-Arg-Arg-Pro-Tyr⌿(CH 2 NH)Ile-Leu-OH (JMV-431), induced dose-dependent antinociceptive responses in the tail-flick test. The effects of levocabastine and of JMV-431 were unaffected by coadministration of the NTS1-specific antagonist 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxy-phenyl)pyrazol-3-yl)carboxylamino]tricyclo)3.3.1.1. 3.7)-decan-2-carboxylic acid (SR48692), confirming that they were NTS2 mediated. In contrast, the antinociceptive effects of NT were partly abolished by coadministration of SR48692, indicating that NTS1 and NTS2 receptors were both involved. These results suggest that NTS2 receptors play a role in the regulation of spinal nociceptive inputs and that selective NTS2 agonists may offer new avenues for the treatment of acute pain.

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“…The neuropeptide neurotensin (N T) exerts important central functions, including hypothermic and naloxone-insensitive analgesic responses after brain injection (Al-Rhodan et al, 1991; for review, see Vincent, 1995). N T interacts with two recently cloned receptors that were originally differentiated on the basis of their affinity for N T and their sensitivity to the antihistaminic drug levocabastine (Schotte et al, 1986).…”

mentioning

confidence: 99%

Identification of the Receptor Subtype Involved in the Analgesic Effect of Neurotensin

et al. 1999

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The neuropeptide neurotensin (NT) elicits hypothermic and naloxone-insensitive analgesic responses after brain injection. Recent pharmacological evidence obtained with NT agonists and antagonists suggests that these effects are mediated by a receptor distinct from the initially cloned high-affinity NT receptor (NTR1). The recent cloning of a second NT receptor (NTR2) prompted us to evaluate its role in NT-induced analgesia. Intracerebroventricular injections in mice of two different antisense oligodeoxynucleotides from the NTR2 markedly decreased NTR2 mRNA and protein and reduced NT-induced analgesia.This effect was specific, because NTR1 levels were unaffected, and sense or scramble oligodeoxynucleotides had no effect. Structure-activity studies revealed a close correlation between the analgesic potency of NT analogs and their affinity for the NTR2 and disclosed potent and selective agonists of this receptor. These data confirm that NTR1 is involved in the NTelicited turning behavior and demonstrate that the NTR2 mediates NT-induced analgesia.

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Structure-antinociceptive activity of neurotensin and some novel analogues in the periaqueductal gray region of the brainstem

Cited by 77 publications

References 39 publications

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

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

Potent Spinal Analgesia Elicited through Stimulation of NTS2 Neurotensin Receptors

Identification of the Receptor Subtype Involved in the Analgesic Effect of Neurotensin

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