Spinal NTS1 receptors regulate nociceptive signaling in a rat formalin tonic pain model

Abstract

Central administration of the neuropeptide neurotensin (NT) was shown to induce antinociceptive responses both spinally and supraspinally. Although NTS2 receptors play an important role in modulating the activity of spinal neurons, we have recently implicated NTS1 receptors in NT's analgesic effects in acute spinal pain paradigms. The current experiments were thus designed to examine the antinociceptive effects of intrathecal administration of NTS1 agonists in formalin‐induced tonic pain in rats. We first established, using immunoblotting and immunohistochemical approaches, that NTS1 receptors were present in small‐ and medium‐sized dorsal root ganglion cells and localized in the superficial layers of the dorsal horn of the spinal cord. We then examined the effects of intrathecal injection of NT (1–15 μg/kg) or NTS1 preferring agonists on the nocifensive response to intraplantar formalin. Both NTS1‐agonists, PD149163 (10–120 μg/kg) and NT69L (1–100 μg/kg), dose‐dependently attenuated the formalin‐induced behaviors. Accordingly, NTS1 agonists markedly suppressed pain‐evoked c‐fos expression in the superficial, nucleus proprius and neck regions of the spinal dorsal horn. The concomitant administration of PD149163 with the NTS1 antagonist SR48692 (3 μg/kg) significantly reversed PD149163‐induced antinociception, confirming the implication of NTS1 in tonic pain. In contrast, NT69L’s analgesic effects were partly abolished by co‐administration of SR48692, indicating that NT69L‐induced effects may also be exerted through interaction with NTS2. These results demonstrate that NTS1 receptors play a key role in the mediation of the analgesic effects of NT in persistent pain and suggest that NTS1‐selective agonists may represent a new line of analgesic compounds.

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

“…There is now compelling evidence demonstrating that the high-affinity NTS1 subtype is involved in antinociception (Wustrow et al, 1995, Smith et al, 1997, Urban and Gebhart, 1997, Buhler et al, 2005, Sarret et al, 2005, Buhler et al, 2008, Roussy et al, 2008. Thus, microinjection of the selective NTS1 agonist PD149163 into the rostral ventromedial medulla produced increases in nociceptive thresholds in the tail-flick tests (Buhler et al, 2005, Buhler et al, 2008.…”

“…The present study was thus conducted to evaluate the implication of NTS1 receptors in opioid-induced analgesia. Since we recently demonstrated that the activation of NTS1 receptors by selective NTS1 agonists reduced the nociceptive behaviors induced by the chemical irritant formalin (Roussy et al, 2008), we used the same experimental model to examine the functional interaction of opioid and NT systems. Specifically, we investigated whether morphine analgesia was affected by NTS1 gene silencing.…”

“…Accordingly, the central role of NT in pain modulation is dependent on the activation of two seventransmembrane domain G-protein-coupled receptors, designed NTS1 and NTS2 (Dobner, 2006, Sarret et al, 2007. Among the studies demonstrating the involvement of NT receptors in nociceptive processing, we recently demonstrated that NTS1 receptors play a key role in mediating the analgesic effects of NT in long-lasting pain (Roussy et al, 2008).…”

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

“…Specifically, N-methyl-Arg, Lys, Trp, and tert-Leu were substituted for Arg, Arg, Tyr, and Ile, respectively (60-64). Likewise, PD149163, a reduced-amide NT [8][9][10][11][12][13] , showed improved metabolic stability after systemic administration and maintained the analgesic activities of the native NT peptide (65)(66)(67). Subsequently, several additional systemically infused but centrally acting analogs (i.e., NT66L, NT69L, NT79, and ABS212) were synthesized by combining N-terminal modifications and incorporation of non-natural amino acids at positions 8, 9, 11, and 12 (63,64,(68)(69)(70)(71).…”

Systemically and Topically Active Antinociceptive Neurotensin Compounds

“…This lack of involvement of opioid systems would be advantageous clinically due to the potential of a reduced abuse liability and the utility of combining neurotensin receptor drugs with other classes of analgesic agents. Although there is general agreement that antinociceptive neurotensin analogs act through neurotensin receptors, it is still uncertain whether these effects are mediated through NTS1, NTS2, or a combination (Boules et al, 2006;Dobner, 2006;Roussy et al, 2008).…”