In the brain of mice,3-iodothyronamine(T1AM) is converted into 3-iodothyroaceticacid(TA1) and it is included within the signaling network connecting thyroid hormone metabolites with histamine

3-iodothyronamine (T1AM) and its oxidative product, 3-iodotyhyroacetic acid (TTA1A), are known to stimulate learning and induce hyperalgesia in mice. We investigated whether i)TA1 may be generated in vivo from T1AM, ii) T1AM shares with TA1 the ability to activate the histaminergic system. Tandem mass spectrometry was used to measure TA1 and T1AM levels in i) the brain of mice following intracerebroventricular (i.c.v.) injection of T1AM (11 μg kg-1), with or without pretreatment with clorgyline, (2.5 mg kg-1 i.p.), a monoamine oxidase inhibitor; ii) the medium of organotypic hippocampal slices exposed to T1AM (50 nM). In addition, learning and pain threshold were evaluated by the light-dark box task and the hot plate test, respectively, in mice pre-treated subcutaneously with pyrilamine (10 mg kg-1) or zolantidine (5 mg kg-1), 20 min before i.c.v. injection of T1AM (1.32 and 11 μg kg-1). T1AM-induced hyperalgesia (1.32 and 11 μg kg-1) was also evaluated in histidine decarboxylase (HDC-/-) mice. T1AM and TA1 brain levels increased in parallel in mice injected with T1AM with the TA1/T1AM averaging 1.7%. Clorgyline pre-treatment reduced the increase in both T1AM and TA1. TA1 was the main T1AM metabolite detected in the hippocampal preparations. Pretreatment with pyrilamine or zolantidine prevented the pro-learning effect of 1.32 and 4 μg kg-1 T1AM while hyperalgesia was conserved at the dose of 11 μg kg-1 T1AM. T1AM failed to induce hyperalgesia in HDC-/- mice at all the doses. In conclusion, TA1 generated from T1AM, but also T1AM, appears to act by modulating the histaminergic system. © 2015 Elsevier B.V. All rights reserved.