SPINAL-CORD PHARMACOLOGY OF ADRENERGIC AGONIST-MEDIATED ANTINOCICEPTION

Abstract

Intrathecal administration of norepinephrine (NE) and .alpha. adrenergic agonists in rats with chronic spinal catheters produced a significant elevation of the nociceptive threshold as measured by hot plate and tail flick. The intrathecal NE effect was dose-dependent and antagonized in a competitive fashion by pretreatment with phentolamine (.alpha. antagonist) but not by propranolol (.beta. antagonist). Intrathecal administration of isoproterenol (.beta. agonist) did not alter the nociceptive threshold. Effective doses of intrathecal NE did not produce demonstrable motor effects. Doses 20 times greater than the maximum analgesic dose produced marked weakness of the hind limbs and tail. The intrathecal NE effect was not antagonized by intrathecal papaverine or bradykinin (vasodilators) or mimicked by angiotensin-II (vasoconstrictor). The intrathecal NE effect was not altered by intrathecal administration of subconvulsant doses of picrotoxin (.gamma.-aminobutyric acid antagonist) or strychnine (glycine antagonist) or by i.p. administration of naloxone (opiate antagonist) or methylsergide (serotonin antagonist). The nociceptive threshold was significantly decreased 1 wk after intrathecal administration of 6-hydroxydopamine, which depleted spinal cord NE by 85%. Intrathecal administration of tyramine (indirectly acting sympathomimetic amine) produced an elevation of the nociceptive threshold in a control group of animals but was less effective in animals pretreated with intrathecal 6-hydroxydopamine. The tyramine effect was antagonized by intrathecal phentolamine. I.v. administration of aminophylline (phosphodiesterase inhibitor) did not potentiate the intrathecal NE effect. The relative antinociceptive potencies of .alpha. adrenergic agonists after intrathecal administration were l-norepinephrine = dl-epinephrine > dl-.alpha.-methyl norepinephrine > clonidine .gtoreq. l-phenylephrine .gtoreq. 3,4-dihydroxytolazoline .gtoreq. oxymetazoline. The relative potencies of intrathecally administered .alpha. antagonists in antagonizing the intrathecal NE effect were phentolamine > phenoxybenzamine > tolazoline .gtoreq. yohimbine.