Blood pressure responses to intrathecal (i.t.) injection of neurochemicals were examined in the fructose-fed rat, an experimental model of metabolic syndrome.Sprague-Dawley rats receiving either tap water or water containing 10% fructose during 8 weeks were anesthetized with sodium pentobarbital. The endocannabinoid anandamide (100 nmol; i.t.) decreased mean blood pressure in control rats (−21.2±6.3 mmHg), but had no effect in fructose-fed animals. Similarly, calcitonin gene-related peptide (CGRP; 0.125 nmol; i.t.) decreased mean blood pressure in control, but not in treated rats. The high fructose diet did not cause significant changes in the pressor effects of i.t. administered noradrenaline (100 nmol) and N-methyl-D-aspartate (30 nmol). The nitric oxide donor sodium nitroprusside (500 nmol, i.t.) induced a brief hypotension followed by a sustained increase in mean blood pressure in control rats; however, this drug only produced pressor effects in fructose-fed animals. The GABAA-receptor agonist muscimol (8.8 nmol, i.t.) and the GABAB-receptor agonist baclofen (100 nmol, i.t.) decreased mean blood pressure 30–35 mmHg, both in control and in fructose-fed rats. Fructose potentiated the pressor effect of i.v. injected noradrenaline, but did not modify the hypotensive responses to i.v. administered sodium nitroprusside and acetylcholine.These results could suggest that, in pentobarbital-anesthetized rats, fructose feeding could alter spinal mechanisms of regulation of preganglionic sympathetic nerve activity. It is proposed that the spinal cord could be involved in the sympathetic dysfunction associated with the metabolic syndrome.