Activation of imidazoline I2 receptor (I2R) by agmatine in adrenal gland lowers plasma glucose through increment in β-endorphin release to stimulate the opioid μ-receptor in streptozotocin-induced diabetic rats (STZ rats). However, the subtype of I2R for agmatine-induced blood glucose lowering effect remains obscure. In the present study, agmatine treatment increased β-endorphin secretion and this effect was blocked by I2R antagonist (BU224) in the isolated adrenal medulla. We further used amiloride, an established blocker of I2AR, to identify the subtype of I2R in adrenal gland. Results showed that agmatine-induced β-endorphin release from adrenal gland was blocked by 0.1 μM amiloride indicating the mediation of I2AR. It was further confirmed that agmatine-induced plasma glucose decrement and plasma β-endorphin increment in STZ rats were blocked by amiloride. However, amiloride failed to modify the action of guanidine, an agonist of I2BR, at the sufficient dose to block β-endorphin secretion. Taken together, the increase of plasma β-endorphin by agmatine in STZ rats through activation of imidazoline I2R was mainly induced by the I2A subtype located in adrenal gland. Thus, imidazoline I2A receptor in the adrenal gland might be applied as a new target for induction of opioid secretion.
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