Vagal afferent control of opioidergic effects in rat brainstem circuits.
We demonstrated recently that increasing the levels of cAMP allows opioids to modulate GABAergic synaptic transmission between the nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV). Using a combination of electrophysiological, immunohistochemical and biochemical approaches, we provide evidence that vagal afferent fibres dampen cAMP levels within the vagal brainstem circuits via tonic activation of group II metabotropic glutamate receptors (mGluRs). Whole-cell patch-clamp recordings were made from identified neurons of the rat DMV. Following chronic vagal deafferentation, the opioid agonist methionine-enkephalin (ME) inhibited the amplitude of evoked IPSC (eIPSC) in 32 of 33 neurons, without exogenous enhancement of cAMP levels. The ME-induced inhibition was prevented by the group II mGluR-selective agonist APDC. Following perfusion with the group II mGluR-selective antagonist EGLU, ME inhibited eIPSC amplitude in brainstem slices of control rats. Immunohistochemical experiments revealed that, following vagal deafferentation, mu-opioid receptors were colocalized on GABAergic profiles apposing DMV neurons; the number of colocalized profiles was significantly decreased by pretreatment with APDC. Radioimmunoassay and Western blot analysis showed that cAMP and phosphorylated cyclic AMP response element binding protein (pCREB) levels in the dorsal vagal complex were increased following vagal deafferentation. Our data show that by tonically dampening the levels of cAMP within the GABAergic synaptic contacts, activated group II mGluRs prevent the modulation of this synapse by endogenous opioids. These data suggest that the plasticity, hence the response, of central circuits controlling the vagal motor outflow to visceral organs is modulated and finely tuned by vagal afferent fibres.
Browning
Kirsteen N
KN
Department of Neuroscience, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.
Zheng
Zhongling
Z
Gettys
Thomas W
TW
Travagli
R Alberto
RA
D000818:Animals; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004744:Enkephalin, Methionine / Q000494:pharmacology; D005071:Evoked Potentials; D041981:Gastrointestinal Tract / Q000294:innervation; D005968:Glutamate Decarboxylase / Q000378:metabolism; D005971:Glutamates / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D009292:Narcotic Antagonists / Q000494:pharmacology; D009433:Neural Inhibition; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D018847:Opioid Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D009435:Synaptic Transmission / Q000502:physiology*; D014628:Vagotomy; D014630:Vagus Nerve / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C097299:4-aminopyrrolidine-2,4-dicarboxylic acid; D005971:Glutamates; D007527:Isoenzymes; D009292:Narcotic Antagonists; D018847:Opioid Peptides; C485765:Oprm1 protein, rat; D018094:Receptors, Metabotropic Glutamate; D017450:Receptors, Opioid, mu; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; C017302:alpha-ethylglutamic acid; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D004744:Enkephalin, Methionine; D011392:Proline; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1