INTRATHECAL ADMINISTRATION OF DYNORPHIN-A AND ITS FRAGMENTS INCREASE HEART-RATE AND ARTERIAL-PRESSURE IN THE URETHANE ANESTHETIZED RAT - MEDIATION BY A NONOPIOID MECHANISM

Intrathecal administration of 6.50 nmol of dynorphin A (dyn A) (1-13) and (1-17) to the ninth thoracic (T9) spinal segment provoked a transient (5-10 min) increase in heart rate (40-60 beats per minute (bpm)) and arterial pressure (20-25 mmHg). Intravenous administration and administration to the second thoracic (T2) segment failed to mimic the effect of T9 administration, suggesting that the cardiovascular effects of T9 administration did not occur via diffusion to the periphery or to the brainstem. The cardioacceleratory and hypertensive responses to T9 dyn A (1-13) administration were prevented by pretreatment with the nicotinic ganglion blocker hexamethonium (10 mg/kg), but were unaffected by bilateral adrenalectomy. These results suggest that the cardiovascular effects of dyn A were mediated predominantly via a sympathetic pathway that does not innervate the adrenal glands. The effects were not antagonized by pretreatment with the opiate receptor antagonist naloxone or by the specific kappa-opiate receptor antagonist nor-binaltorphimine, suggesting that they were not mediated via activation of kappa-opiate receptors. Further support for this conclusion was provided by experiments demonstrating that dyn A (3-13) (30 nmol), a dynorphin fragment which is devoid of kappa-activity, mimicked the effect of dyn A (1-13), whereas administration of the synthetic kappa-agonist U50, 488H (100 nmol), failed to elicit effects similar to those provoked by dyn A (1-13). It is concluded that the cardiovascular effects of intrathecal dyn A administration are mediated via a nonopioid mechanism.