title: EphB2 reverse signaling regulates learned opiate tolerance via hippocampal function.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Sofia
authors.initials: S
authors.lastname: Huroy
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Ashlin
authors.initials: A
authors.lastname: Kanawaty
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Lilia
authors.initials: L
authors.lastname: Magomedova
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
authors.affiliation: Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Susan R
authors.initials: SR
authors.lastname: George
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Derek
authors.initials: D
authors.lastname: van der Kooy
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada. Electronic address: jeff.henderson@utoronto.ca.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Henderson
mesh_terms: D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004361:Drug Tolerance / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018345:Mice, Knockout; D009020:Morphine / Q000493:pharmacokinetics / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D059226:Nociceptive Pain / Q000188:drug therapy / Q000378:metabolism; D058748:Pain Perception / Q000187:drug effects / Q000502:physiology; D036183:Receptor, EphB2 / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013373:Substance P / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D013373:Substance P; D009020:Morphine; C586311:Ephb2 protein, mouse; D036183:Receptor, EphB2; D015740:Calcitonin Gene-Related Peptide
keywords: Competitive interference; Eph receptors; Gene knockout; Morphine; Passive avoidance