Evidence for additional neurotensin receptor subtypes: Neurotensin analogs that distinguish between neurotensin-mediated hypothermia and antinociception

Neurotensin (NT), a tridecapeptide, is a neurotransmitter that elicits potent effects including hypothermia and antinociception in mice and rats. To date, there are two types of the neurotensin receptor (NTR) that have been molecularly cloned from the rat. However, several lines of evidence suggest the presence of additional NTR subtypes. We have identified a NT analog of the NT(8-13) fragment, NT27, that selectively causes only the hypothermic response in vivo, when microinjected into the periaqueductal gray (PAG) of rats. A dose of 18 nmol of NT or NT27 caused a body temperature lowering of 1.8 and 1.2°C, respectively. This same dose of NT or NT27 yielded a hotplate maximum physiological effect of 75% and 25%, respectively. Interestingly, despite its high K(D) (620 nM) at the cloned NTR-1, NT27-I (the iodinated form of NT27) exerted a potent hypothermic effect even at a very low dose (0.6 nmol). Equally intriguing, was that NT24, a sterioisomer of NT27, with a much higher affinity (K(D) = 0.5 nM) at NTR-1, did not selectively induce hypothermia in mice, but did selectively induce hypothermia in rats.