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Effects of isovaline and involvement of metabotropic group ii glutamate receptors

University of British Columbia

This thesis is comprised of manuscripts describing effects of isovaline, metabotropic GABAB agonist, baclofen, and metabotropic glutamate (mGlu II) agonist, LY354740, on peripheral and central neurons. Our laboratory studies previously demonstrated analgesic properties of isovaline acting on peripheral GABAB receptors while in brain slices, isovaline acted as atypical GABAB agonist. Peripheral GABAB and mGlu II receptors belong to same family of G-protein-coupled receptors. We examined if isovaline activated peripheral mGlu II receptors that inhibit nociception. We assessed post- and presynaptic effects of isovaline, with comparison to baclofen and LY354740 on neurons of somatosensory thalamus. We compared effects of isovaline, baclofen and LY354740 on electrically evoked contractions of guinea-pig ileum, a standard assay for GABAB receptors. In manuscript one, we hypothesized that mGlu II receptors mediate isovaline analgesia. We utilized a model of pain induced by prostaglandin-E2 which sensitizes primary afferent fibers in hindpaw of mice. Isovaline produced analgesia which was blocked by mGlu II antagonist (LY341495). Therefore isovaline activated peripheral mGlu II receptors, in addition to GABAB receptors. In manuscript two, we hypothesized that isovaline activates presynaptic GABAB and mGlu II receptors, thereby inhibiting GABA and glutamate release. We studied effects of isovaline, baclofen and LY354740 on inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs) in thalamocortical neurons. We determined effects on electrically stimulated release of transmitters which we confirmed as producing GABAergic and glutamatergic currents. The agonists decreased amplitudes of IPSCs and EPSCs during selective blockade of other postsynaptic currents, without affecting decay-time constants. GABAB antagonist (CGP52432) and LY341495 blocked isovaline effects, implicating GABAB and mGlu II receptors in transmitter release inhibition. In manuscript three, we hypothesized that isovaline activates ileal GABAB and mGlu II receptors. Isovaline decreased amplitude of muscle contractions and increased resting tension. CGP52432 antagonized baclofen-induced decreases in amplitude and tension, but not isovaline effects. LY354740 had no effect. These findings suggest novel targets for isovaline-like compounds in ileum. The thesis demonstrates for the first time that isovaline produces analgesia in hindpaw and presynaptic inhibition in thalamus by activating mGlu II in addition to GABAB receptors, while isovaline receptors are distinct from GABAB receptors in ileum.

Text

2019-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/64787

Pharmacology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/