Date of Award


Degree Type


Degree Name

Doctor of Philosophy


Interactions with the A{dollar}\sb1{dollar} subtype of adenosine receptors in the enteric nervous system (ENS) have previously been shown to lead to inhibition of ACh release from nerves of the myenteric plexus. Similar inhibition of release of the major contractile neuropeptide, substance P (SP), has only been demonstrated indirectly. Although the mechanism of adenosine-mediated neuroinhibition in the CNS has been elucidated, similar mechanisms in the ENS remain unknown.;The objective of this thesis was to directly examine the inhibitory effects of A{dollar}\sb1{dollar} receptor interactions on the release of substance P from enteric neurons and to identify the intracellular mechanisms involved in this inhibition.;The contractile response of the field-stimulated guinea pig longitudinal muscle-myenteric plexus (LMMP) preparation was inhibited in a dose-dependent manner by subtype-selective adenosine analogs. The potency order of the agonists indicated actions at the A{dollar}\sb1{dollar} receptor subtype. This was confirmed by blockade of agonist-mediated inhibition using subtype-selective adenosine receptor antagonists and subsequent Schild analysis. Depolarization of perifused enteric nerve varicosities (synaptosomes) using elevated extracellular potassium ({dollar}\rm\uparrow\lbrack K\sp+\rbrack\sb{lcub}o{rcub}{dollar}) clearly evoked the Ca{dollar}\sp{lcub}2+{rcub}{dollar}-sensitive release of substance P-like immunoreactivity (SP-LI) from these entities. Perifusion with adenosine analogs led to a concentration-dependent inhibition of SP-LI release with the potency order again indicating A{dollar}\sb1{dollar}-mediated effects. The A{dollar}\sb1{dollar}-selective adenosine analog, CPA, inhibited {dollar}\rm\uparrow\lbrack K\sp+\rbrack\sb{lcub}o{rcub}{dollar}-evoked release of SP-LI from perifused dissociated enteric ganglia by a mechanism that was insensitive to pre-incubation with pertussis toxin. CPA-mediated inhibition was generally not altered in the presence of K{dollar}\sp+{dollar} channel blockers or inhibitors of protein kinase C activity. In addition, the actions of CPA were not mimicked by K{dollar}\sp+{dollar} channel openers or phorbol esters. CPA-mediated inhibition was abolished in the presence of Cl{dollar}\sp-{dollar} channel blockers and by replacement of {dollar}\rm\lbrack Cl\sp-\rbrack\sb{lcub}o{rcub}{dollar} with an impermeable anion.;These data provide evidence that A{dollar}\sb1{dollar} receptor-mediated inhibition of SP-LI from neurons of the myenteric plexus is mediated by activation of Cl{dollar}\sp-{dollar} channels and subsequent Cl{dollar}\sp-{dollar} influx. These actions are not mediated by pertussis toxin-sensitive inhibitory g-proteins.



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