Low Molecular Weight Neurotrophin-3 Mimetics, Distinct in the Pattern of Activation of Postreceptor Signaling, Attenuate the Manifestations of Morphine Withdrawal in Rats in Different Ways

The accumulated data suggest that changing activity levels of tyrosine kinase receptor signaling pathways may regulate opiate-related neuroadaptation of the noradrenergic system. Neurotrophin-3 (NT-3) interacts with tropomyosin receptor kinases (TRK), binding predominantly to TRKC receptors, which are expressed in noradrenergic neurons of locus coeruleus. Taking into account the difficulties of delivering full-size neurotrophins to the CNS after systemic administration, low-molecular mimetics of the 4th loop of NT-3, hexamethylenediamide bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) (GTS-301) and hexamethylenediamide bis-(N-γ-hydroxybutyril-L-glutamyl-L-asparagine) (GTS-302), interacting with TRKC and TRKB receptors, were synthesized. The aim of this work was a comparative study of NT–3 mimetics effect on the manifestations of morphine withdrawal symptoms in albino rats with opiate dependence, as well as the features of activation of postreceptor signaling pathways by NT–3 mimetics. The dipeptides GTS-301 and GTS-302 after acute administration at doses of 0.1, 1.0 and 10.0 mg/kg, i.p., had a dose-dependent effect on the specific signs of morphine withdrawal with the most effective dose of 1.0 mg/kg. The maximum reduction in the total morphine withdrawal syndrome index for GTS-301 was 31.3% and for GTS-302 – 41.4%. Unlike GTS-301, GTS-302 weakened mechanical allodynia, reducing tactile sensitivity. When studying the activation of postreceptor signaling pathways by NT-3 mimetics on a culture of HT-22 hippocampal cells, it was shown that they had a different pattern of postreceptor signaling: GTS-302 (10⁻⁶ M), like NT-3, activated all three MAPK/ERK, PI3K/AKT/mTOR and PLCy1, while GTS-301(10⁻⁶ M) – only MAPK/ERK- and PLCy1. Thus, the revealed features of attenuation of morphine withdrawal syndrome in rats after acute GTS-301 and GTS-302 administration may be associated with a different pattern of activation of postreceptor pathways.