Inhibition in the spinal cord is a crucial mode of opioid action leading to analgesia as intrathecal injection of µ-opioid receptor (MOR) antagonists abolishes the analgesic action produced by systemic opioid administration. Opioids bind to spinal MORs expressed presynaptically on central terminals of primary afferent nociceptive nerve fibers and postsynaptically on superficial dorsal horn neurons. We have shown that opioids specifically depress neurotransmitter release from nociceptive Aδ- and C-fibers via presynaptic inhibition mediated by an inhibition of N-type, and to a lesser extent of P/Q-type voltage-dependent Ca2+-channels. We found, in addition, a direct inhibition of the downstream transmitter release machinery by opioids as revealed by two-photon imaging of styryl dye destaining [1].
Furthermore, the presynaptic inhibition at C-fibers by opioids prevents the induction of LTP at these synapses. Strong noxious stimuli that normally would induce LTP at C-fibers and thus hyperalgesia no longer do so under the protection of opioids. This is a cellular mechanism of pre-emptive analgesia that is clinically used in an attempt to prevent some forms of pain chronicity.
Another important finding from our group is that opioids not only have an acute analgesic effect and may prevent the development of persistent pain, but even may reverse an established LTP at C-fiber synapses. It is generally assumed that opioids depress pain only as long as they act on their specific receptors (reversible depression at C-fiber synapses). But we could show in a recent publication that a brief, high dose opioid treatment not only temporarily depressed synaptic strength at synapses in the spinal cord dorsal horn but induced a long-lasting reversal of LTP (depotentiation). Depotentiation involved Ca2+ dependent signaling and a normalization of the phosphorylation state of spinal AMPA receptors. Furthermore, opioid treatment induced reversal of hyperalgesia in behaving animals [2].
The use of opioids might, however, be limited by tolerance or opioid-induced hyperalgesia which is a characteristic symptom of the withdrawal syndrome that can be seen when opioids are withdrawn abruptly, either in drug addicts or in pain patients. We have now identified a novel mechanism of opioid withdrawal hyperalgesia. The abrupt withdrawal from various clinically used opioids induces LTP at C-fiber synapses [3,4]. This phenomenon involves the activation of postsynaptic G-protein coupled receptors, a postsynaptic Ca2+ rise and the activation of postsynaptic NMDA receptors. The opioid withdrawal LTP can be prevented by a tapered withdrawal regimen. Interestingly, fentanyl- and morphine-induced withdrawal LTP involved additional activation of descending, facilitatory serotonergic pathways [3]. Hence, combining blockade of spinal NMDA and 5-HT3-receptors may be a highly effective treatment option. These findings may guide clinicians in their steps to avoid hyperalgesia upon termination of opioid treatments.
