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

Abstract

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.

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

“…administration of ANG2002 (5 mg/kg). As previously observed (30,41), the baseline pain thresholds in both genotypes were not significantly different from thresholds in WT littermates. Injection of ANG2002 i.v.…”

“…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).…”

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

“…These results confirm the importance of the neurotensinergic system in the control of pain modulation. The involvement of both NTSR1 and NTSR2 in the effect of NT on analgesia has been largely demonstrated in the literature either by using ligands selective for each receptor (Sarret et al, 2005; Smith et al, 2012) or by using mice in which NTSR1 or NTSR2 genes have been deleted (Maeno et al, 2004; Roussy et al, 2010). …”

Neurotensin and its high affinity receptor 1 as a potential pharmacological target in cancer therapy

“…Mice were also less responsive or sensitive to exogenous agents or conditions. NTSR1 ko mice were less sensitive to the anorectic effects caused by leptin (Kim et al, 2008), and less responsive to morphine-induced analgesia (Roussy et al, 2010). Experiments with NTSR1- and NTSR2-deficient mice indicate a role in the regulation of ethanol consumption.…”