An NTS2 Analog Enhances the Analgesic Effects of Morphine in an Animal Model of Persistent Pain and Does not Exhibit Tolerance

The analgesic efficacy of neurotensin agonists depends on their activation of two receptor subtypes, NTS1 and/or NTS2. In this study we determined the role of NTS2 in an animal model of persistent pain (intraplantar injection of formalin) with the use of the NTS2-selective analog, NT79 and NTS2-knockout mice (NTS2 -/). Wild type (WT) and NTS2 -/mice were pretreated with NT79 and tested for formalin-induced lifting and biting. Additionally, the effect of repeated administration of NT79 and morphine alone and in combination was determined in WT mice. Intraplantar injection of formalin produced the typical biphasic nociceptive response of this persistent pain model. Formalin evoked lower pain intensity in NTS2 -/mice as compared to that for WT mice. Pretreatment with NT79 attenuated formalininduced nociception throughout phase II in the WT mice, and in early phase II in the NTS2 -/mice. Lifting and biting responses were attenuated, indicating spinal and supra-spinal modulation of persistent nociception. More importantly, repeated injection of NT79 enhanced, while that of morphine reduced their antinociceptive effects, respectively. Subchronic co-administration of NT79 and morphine enhanced the analgesic effect over either drug alone. These data support the role of NTS2 in modulating formalin-induced pain. Additionally, these data provide a rationale for the potential therapeutic role of NTS2-selective analogs in chronic pain management alone or in combination with morphine and without the development of tolerance.