Sympatholytic delta-2 opioid receptors moderate ganglionic vasomotor control

Abstract

This study tested the hypothesis that enkephalin increases femoral vascular conductance via the delta-2 phenotype of the opioid receptor (DOR-2) within peripheral sympathetic ganglia. Graded pulses of methionine–enkephalin (ME) were administered (0.03–10 μg/kg) into the terminal aorta of anesthetized dogs proximal to lumbar arteries that perfuse vasomotor ganglia regulating femoral blood flow. Femoral vascular conductance increased sharply (ED50 = 2.6 × 10−9 mol/kg) accompanied by declines in arterial pressure and femoral vascular resistance. A dose-related increase in arterial pressure preceded each subsequent fall in pressure. The DOR-2 antagonist, naltriben (NTB), abrogated the hyperemic effect of ME (ID50 = 1.4 × 10−9 mol/kg). DOR-1 blockade (BNTX) was five-fold less effective. The hyperemic effect of ME was also enhanced when sympathetic activity was reflexly increased by bilateral carotid occlusion. The DOR-2 agonist, deltorphin II, produced exaggerated increases in conductance compared with ME that were also reduced by DOR-2 blockade. DOR-1 blockade eliminated the initial pressor responses, exaggerated the subsequent depressor response, increased baseline femoral conductance 10-fold and shifted the ME-mediated hyperemic threshold one dose lower from 0.3 to 0.1 μg/kg, providing indirect support for a competing DOR-1-mediated constriction. Extended exposure to DOR-1 blockade lowered the maximal ME increase in conductance by 30%, suggesting that BNTX reduces the available pool of DOR receptors. In summary, enkephalin mediates a robust hyperemic effect through sympatholytic ganglionic DOR-2 receptors and DOR-1 antagonist studies provide indirect evidence for constituent opposition from a proposed DOR-1-mediated sympathotonic constrictor pathway.