Alterations in nociception and body temperature after intracisternal administration of neurotensin, beta-endorphin, other endogenous peptides, and morphine.

Nemeroff, Charles B.; Osbahr, Albert J.; Manberg, Paul J.; Ervin, Gregory N.; Prange, Arthur J.

doi:10.1073/pnas.76.10.5368

Cited by 140 publications

(101 citation statements)

References 25 publications

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“…The availability of a new class of drug would have many advantages. Neurotensin has long been known to have many actions, including analgesia (Clineschmidt and McGuffin, 1977;Nemeroff et al, 1979;Boules et al, 2006;Dobner, 2006). Clearly, these early reports documented an antinociceptive response.…”

Section: Discussionmentioning

confidence: 99%

Systemically and Topically Active Antinociceptive Neurotensin Compounds

Rossi¹,

Matulonis²,

Richelson³

et al. 2010

J Pharmacol Exp Ther

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Neurotensin is a neurotransmitter/modulator with a wide range of actions. Using a series of 10 stable analogs, we have examined neurotensin antinociception in mice. By incorporating (2S)-2-amino-3-(1H-4-indoyl)propanoic acid (L-neoTrp), a series of neurotensin analogs have been synthesized that are stable in serum and are systemically active in vivo. When administered in mice, they all were antinociceptive in the radiant heat tail-flick assay. Time-action curves revealed a peak effect at 30 min and a duration of action ranging from 2 to 4 h. Dose-response curves revealed that two compounds were partial agonists with maximal responses below 75%, whereas all of the remaining compounds displayed a full response. Overall, the compounds were quite potent, with ED 50 values similar to those of opioids. At peak effect, the ED 50 values ranged from 0.91 to 9.7 mg/kg s.c. Two of the analogs were active topically. Together, these studies support the potential of neurotensin analogs as analgesics. They are active systemically and by using them topically, it may be possible to avoid problematic side effects, such as hypothermia and hypotension.

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Section: Discussionmentioning

confidence: 99%

Systemically and Topically Active Antinociceptive Neurotensin Compounds

Rossi¹,

Matulonis²,

Richelson³

et al. 2010

J Pharmacol Exp Ther

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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: 99%

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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“…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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Alterations in nociception and body temperature after intracisternal administration of neurotensin, beta-endorphin, other endogenous peptides, and morphine.

Cited by 140 publications

References 25 publications

Systemically and Topically Active Antinociceptive Neurotensin Compounds

Systemically and Topically Active Antinociceptive Neurotensin Compounds

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

Potent Spinal Analgesia Elicited through Stimulation of NTS2 Neurotensin Receptors

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