THE ROLE OF NITRIC-OXIDE IN OPIOID-INDUCED PIAL ARTERY VASODILATION

The present study was designed to investigate the role of nitric oxide (NO) and the production of cGMP in the vasodilator response to opioid agonists in newborn pigs equipped with a closed cranial window. Methi onine-enkephalin (10(-8), 10(-6) M), an endogenous mu opioid agonist, produced pial artery dilation that was attenuated by L-nitroarginine ( LNA, 10(-6) M), an NO synthase inhibitor (10 +/- 1 vs. 4 +/- 1 and 16 +/- 1 vs. 7 +/- 1% for 10(-8), 10(-6) M methionine-enkephalin, respect ively). Methionine-enkephalin-induced vasodilation was associated with increased cortical periarachnoid CSF cGMP and these changes in CSF cG MP were attenuated by LNA (354 +/- 11 and 596 +/- 32 vs. 278 +/- 13 an d 266 +/- 19 fmol/ml for control and methionine-enkephalin 10(-6) M be fore and after LNA, respectively). Leucine enkephalin, an endogenous d elta agonist, elicited similar changes in pial diameter and CSF cGMP w hile dynorphin, an endogenus k agonist, produced dilation associated w ith large increases in CSF cGMP (374 +/- 18 vs. 1054 +/- 45 fmol/ml fo r central and dynorphin 10(-6) M, respectively). Vascular and biochemi cal changes for these two opioids were similarly attenuated by LNA. Th e synthetic selective opioid receptor agonists, DAMGO, DPDPE, deltorph in, and U50,488H (10(-8), 10(-6) M) mu, delta(1), delta(2), and kappa agonists, respectively also elicited increases in pial artery diameter and CSF cGMP that were similarly attenuated by LNA. The coadministrat ion of L-Arg (10(-3) M) with LNA partially restored opioid-induced pia l artery dilation and associated changes in CSF cGMP whereas D-Arg (10 (-3) M) coadministered with LNA did not restore opioid-induced vascula r and biochemical changes. These data indicate that NO contributes to opioid-mediated pial artery vasodilation.