MECHANISMS OF NEUROTENSIN-DRIVEN HYPOTHERMIC AND HYPOTENSIVE RESPONSES

Neurotensin (NT) is an endogenous tridecapeptide that induces a prolonged, dose-dependent decrease in core body temperature via activation of the two G-protein coupled receptors, NTS1 and NTS2. Harnessing NT’s hypothermic properties may offer a therapeutic strategy for inducing protective hypothermia in clinical settings like cardiac arrest or ischemic stroke. However, the concurrent induction of hypotension by NT and its analogs has limited their therapeutic application. Elucidating the mechanisms that differentially mediate NT-induced hypothermia and hypotension is therefore critical for therapeutic advancement. Here, we hypothesized that histamine selectively contributes to NT-induced hypotension but not to hypothermia. Using implemented telemetry probes in rats, we simultaneously monitored blood pressure and core body temperature, following administration of the NT receptor agonist HPI-363. Pharmacological modulation of histamine signaling was achieved using the H1 receptor antagonist cetirizine and the mast cell activator compound 48/80. Peripheral manipulation of histamine signaling did not alter HPI-363-induced hypothermia, supporting a central mechanism underlying NT-mediated thermoregulation. Ongoing studies will further delineate central versus peripheral contributions by measuring physiological responses to intracerebroventricular HPI-363 in the presence of peripheral or central cetirizine. Together, these findings advance our understanding of the distinct pathways governing NT’s physiological effects and support the feasibility of selectively engaging NT-driven hypothermia while minimizing hypotension. This mechanistic insight will inform the development of safer more targeted NT-based therapeutics for neuroprotection.