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Behav Brain Res. 2016 Mar 1;300:85-96. doi: 10.1016/j.bbr.2015.09.023. Epub 2015 Sep 25.

EphB2 reverse signaling regulates learned opiate tolerance via hippocampal function.

Author information

1
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
2
Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
3
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
4
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada. Electronic address: jeff.henderson@utoronto.ca.

Abstract

Despite significant progress, many uncertainties remain regarding molecular and cellular mechanisms governing opiate tolerance. We report that loss of EphB2 receptor reverse signaling results in a marked acceleration of morphine tolerance in vivo. EphB2 null mice exhibited no significant difference in brain or blood morphine metabolism, mu opiate receptor affinity or binding capacity. Motor and sensory performance for EphB2 null mice was also comparable to controls for both morphine naïve or tolerized states. Regional distributions of mu opioid receptor, CGRP and substance P were also unaltered in EphB2 null mice. However EphB2 null mice, but not animals homozygous for kinase dead version of EphB2, exhibited significant modification of context-dependent anti-nociceptive responses following chronic morphine treatment. To verify the changes seen in EphB2 null mice arise from impairment of hippocampal learning, discreet bilateral lesions of the dorsal hippocampus were produced in wildtype mice demonstrating striking similarities to that seen in EphB2 null mice for opiate-dependent behavior. The results demonstrate that EphB2 reverse signaling plays a unique and requisite role in inhibiting the development of opiate-dependent tolerance in vivo.

KEYWORDS:

Competitive interference; Eph receptors; Gene knockout; Morphine; Passive avoidance

PMID:
26408450
DOI:
10.1016/j.bbr.2015.09.023
[Indexed for MEDLINE]

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