Influence of stimulation train length on the opioid-induced inhibition of norepinephrine release in the rabbit ear artery

In perfused segments of rabbit ear artery the effects of opioid agonists on vasoconstrictor responses to adrenergic nerve stimulation and stimulation-evoked [3H]norepinephrine overflow were compared using trains of 8, 40 or 120 monophasic pulses at 8 Hz with 1 msec duration and 40 V amplitude. Both delta selective peptides, [D-Ala2, D-Leu5]-enkephalin, met-enkephalin and leu-enkephalin, and preferential kappa ligands, dynorphin1-13 and ethylketocyclazocine, significantly reduced the vasoconstriction evoked by 8 pulses at 8 Hz. The magnitude of this effect was inversely related to the stimulus train length. In most cases, opioid agonists were highly effective with short stimulus trains, but failed to decrease vasoconstrictor responses by more than 10 to 15% with trains of 120 pulses at 8 Hz. In good correlation with these data, in tissue preincubated with [3H]norepinephrine the inhibitory effect of opioids on the tritium overflow evoked by 8 or 120 pulses at 8 Hz was inversely proportional to the length of stimulation. Our findings confirm that opioid agonists interact with a heterogeneous prejunctional receptor population to modulate the action potential-evoked release of norepinephrine in the isolated ear artery of the rabbit. This modulation is more pronounced at the beginning of a stimulus train when the negative feedback inhibition of norepinephrine release is still not fully operative. It is suggested that the physiological role of opioid peptides could be more significant during a short rather than a prolonged vasoconstriction.