Presynaptic ?2-adrenoceptor, opioid ?-receptor and adenosine A1-receptor interactions on noradrenaline release in rabbit brain cortex

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Abstract
The interaction of presynaptic, release-inhibiting α2-adrenoceptors, opioid κ-receptors and adenosine A1-receptors was studied in slices of the occipito-parietal cortex of the rabbit. The slices were preincubated with 3H-noradrenaline and then superfused and stimulated electrically twice for 2 min each (S1, S2). The stimulation-evoked overflow of tritium was taken to reflect action potential-evoked release of noradrenaline. One of two release-modulating compounds to be examined for interaction was kept in the medium throughout superfusion, the other one was added before S2. In many experiments, the stimulation parameters were adjusted (frequency 0.5–7 Hz; voltage drop 2–5 V/cm) in order to obtain similar reference release (S1) values despite the presence of the first release-modulating compound. The selective κ-receptor agonist ethylketocyclazocine (EK) attenuated markedly the release-inhibiting effects of the α2-adrenoceptor-selective agonists clonidine and α-methylnoradrenaline as well as the release-facilitating effect of the α2-adrenoceptor-selective antagonist yohimbine. The attenuation occurred both when the parameters of electrical stimulation were kept constant and when they were adjusted to obtain similar S1 release values. The selective A1-receptor agonist R-N6-phenylisopropyladenosine (PIA) also attenuated the effects of clonidine and yohimbine. Conversely, clonidine attenuated and yohimbine enhanced the release-inhibiting effect of PIA. Yohimbine also enhanced the release-facilitating effect of the adenosine receptor antagonist 8-phenyltheophylline. Again, these changes occurred both at constant stimulation parameters and when stimulation parameters were adjusted. EK attenuated the release-inhibiting effect of PIA, and conversely PIA attenuated the effect of EK, both at constant and at adjusted parameters of electrical stimulation. The release-inhibiting effects of tetrodotoxin and Cd2+ remained unchanged in the presence of clonidine or EK. These results demonstrate mutual interactions between presynaptic a2-, opioid K- and adenosine A1-receptors. As soon as any one of the three systems is activated, the inhibition due to activation of either of the two remaining systems is blunted. The interactions are not a consequence of the change in release per se that the first receptor ligand inevitably produces. α-Adrenoceptors interact with opioid κ-receptors in a similar manner, independently of the chemical nature (imidazoline or phenylethylamine derivative) of the α-agonist used. The interaction is specific for release-modulating receptors and does not extend to Na+ ar Ca2+ channel blockers. It may occur at the level of the receptors themselves or at the post-receptor transduction mechanisms.