Selective antagonism of the antinociceptive effect of intrathecally applied alpha adrenergic agonists by intrathecal prazosin and intrathecal yohimbine.

We have attempted to define the alpha adrenoceptor subtype(s) on which intrathecally applied alpha adrenergic agonists act to produce their antinociceptive effect. The potencies of intrathecal (i.t.) prazosin or i.t. yohimbine to antagonize the elevations of thermal nociceptive threshold induced by i.t. 2-[2,6-diethylphenylamino]-2-imidazoline (ST-91), methoxamine or norepinephrine (NE) were determined in the rat. Tail-flick and hot plate tests were used to determine thermal nociceptive threshold. At the ID50 level, the alpha-2 selective antagonist yohimbine was significantly more potent than the alpha-1 selective antagonist prazosin at blocking the analgesia produced by the alpha-2 selective agonist ST-91, whereas prazosin was significantly more potent than yohimbine at antagonizing the analgesia produced by the alpha-1 selective agonist methoxamine or by the nonselective alpha agonist NE. Analgesic doses of methoxamine evoked a readily observable disturbance of motor and autonomic function, whereas such effects were not observed after analgesic doses of ST-91 or NE. Both i.t. methoxamine and i.t. ST-91 elevated thermal nociceptive threshold in rats depleted of lumbar spinal cord NE by pretreatment 7 days before with i.t. 6-hydroxydopamine. Our results suggest that stimulation of either one of two separate populations of postsynaptic spinal alpha adrenoceptors will inhibit spinal nociceptive transmission. One of these populations appears to be composed of alpha-2 adrenoceptors. The subtype classification of the alpha adrenoceptors composing the other population remains unclear.