Noradrenergic inhibition of the release of substance P from the primary afferents in the rabbit spinal dorsal horn.

To investigate pre-synaptic influence of the descending noradrenergic system on the primary afferents containing substance P (SP), effects of noradrenergic manipulations on the in situ release of immunoreactive SP (iSP) from the dorsal horn were examined in the thalamic rabbit. Local application of noradrenaline (10 microM) to the dorsal horn produced complete inhibition of the noxious mechanical stimuli-evoked release of iSP. This effect was reversed by yohimbine (the more selective alpha 2-blocker, 10 microM) and partially antagonized by prazosin (the more selective alpha 1-blocker, 10 microM). The resting release of iSP was not affected by noradrenaline. The noxious mechanical stimuli-evoked release of iSP was significantly increased by acute spinal transection and local application of yohimbine (10 microM) alone to the dorsal horn. Prazosin (10 microM) slightly increased the evoked iSP release, and a beta-blocker metoprolol did not affect it. These results suggest that the nociceptive primary afferents containing SP are tonically inhibited by the descending noradrenergic system linked to alpha-adrenoceptors, and that such alpha-adrenoceptors located on the primary afferent terminals may be one of the sites of action of noradrenaline spinal analgesia. In contrast to the evoked iSP release, the resting iSP release was increased only by acute spinal transection and not by yohimbine, prazosin and metoprolol. All these observations suggest that tonic inhibition in propriospinal neurons containing SP is mediated by a non-noradrenergic system.