Multiphasic effect of morphine on the release of substance P from rat trigeminal nucleus slices

It is generally accepted that morphine acts presynaptically to inhibit substance P (SP) release from afferent terminals in the trigeminal nucleus. Recent studies, however, provide evidence that opioids produce both inhibitory and excitatory effects on SP release which are concentration- and receptor subtype-dependent. In the present study, we have examined a wide range of morphine concentrations on K⁺ -evoked SP release from rat trigeminal nucleus caudalis slices. Immunoreactive SP was measured in perfusates. Morphine produces multiphasic effects on K⁺-evoked SP release without affecting basal release. A very low nannomolar concentration (1 nM) suppressed release, higher nanomolar concentrations (100-300 nM) facilitated release, a low micromolar concentration (3 μM) suppressed release, and a higher micromolar concentration (30 μM) facilitated release. These effects were abolished by opioid receptor blockade with naloxone (30 nM). Thus, morphine produces a complex bi-directional modulation of SP release from TNC which is concentration- and possibly receptor subtype-dependent.