Analgesic synergy of neurotensin receptor subtype 2 agonist NT79 and morphine

Abstract

Neurotensin (NT) is a tridecapeptide with naloxone-independent analgesic action. NT exerts its effects through three molecularly cloned receptor subtypes, NTS1, NTS2, and NTS3. The analgesic efficacy of NT agonists depends on their activation of NTS1 and/or NTS2. NT79 is an NTS2-selective agonist without hypothermic and hypotensive effects, produces analgesic effects in animal models of visceral (writhing), but not thermal (hot plate) pain. This study extends previous study with NT79 to test its efficacy in an animal model of persistent pain (formalin test) and to determine whether there is analgesic synergy between NT79 and morphine on visceral and persistent pain. NT79 enhanced the analgesic potency of morphine in the writhing test. In the persistent pain model, NT79 and morphine attenuated formalin-induced lifting and biting during the inflammatory phase. NT79 and morphine alone significantly blocked the lifting but not the biting response, which involves the activity of spinal nociceptive circuits. However, the combination of NT79 and morphine attenuated both lifting and biting responses, results indicating both spinal and supraspinal modulation of persistent nociception. Isobolographic analyses show analgesic synergism between NT79 and morphine in persistent pain, thus providing a promise of therapy for pain while minimizing adverse effects associated with morphine use.

Diverse Roles of Neurotensin Agonists in the Central Nervous System

“…Since the NTS1-selective (NT72), and non-selective (NT69L) NT agonists attenuate visceral nociception, it is suggested that both NTR subtypes are involved in mediating visceral analgesia and their roles appear to be NT analog dependent (Smith et al, 2012). Additionally, the NTS2-selective analog, NT79, reduces formalin-induced pain and does so in synergy with morphine (Boules et al, 2011a). Further evidence for the involvement of NTS2 in reducing persistent pain comes with the use of knockout mice.…”

Identification of 1-({[1-(4-Fluorophenyl)-5-(2-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}amino)cyclohexane Carboxylic Acid as a Selective Nonpeptide Neurotensin Receptor Type 2 Compound

“…NT-mediated analgesia has been demonstrated with compounds selective for both the NTS1 and NTS2 receptors as well as nonselective compounds. 23−28 Beyond this, there is now substantial evidence that both NTS1 and NTS2 can mediate relief from chronic or neuropathic pain. 29 This type of pain is difficult to treat with current drugs and does not always respond well to opioid therapy.…”

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

“…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).…”