Synaptic long-term potentiation after opioid withdrawal

Opioids are highly effective analgesics that represent the gold standard for the treatment of moderate to severe pain. Paradoxically opioids may also enhance the sensitivity to noxious stimuli. For example, upon withdrawal from opioids pain sensitivity may be elevated beyond pre-drug levels. This form of opioid-induced hyperalgesia (OIH) is a manifestation of physical opioid dependence. The mechanisms leading to OIH are not fully understood. In the preceding funding project we have discovered a novel action of opioids [1]; the long-term potentiation after opioid withdrawal (withdrawal LTP) at synapses between nociceptive C-fibres and neurons in lamina I of the spinal dorsal horn. At this critical synaptic relay LTP may also be induced by strong or continuous noxious stimuli, as shown in our previous FWF-funded projects [2;3]. This activity-dependent form of LTP is now considered a cellular model of memory traces for pain [4]. The present grant proposal aims at identifying the properties and functions of withdrawal LTP. In particular we wish to understand which conditions favour the induction of withdrawal LTP, which opioid receptors are involved and which types of lamina I neurons may express withdrawal LTP. We will further explore the signalling pathways involved. For example, we will test the hypothesis that opioid receptors on glial cells including astrocytes may be involved. We will test if the release of gliotransmitters such as cytokines and neurotrophic factors is essential for the induction of withdrawal LTP. Our pilot study [1] has already revealed that activation of G-protein coupled receptors and a rise in free cytosolic Ca2+ in the postsynaptic neuron is indispensable for the induction of withdrawal LTP. Now we plan to identify the nature of the critical G-protein coupled receptors and to explore the Ca2+-dependent signalling pathways. Finally we will evaluate the role of these cellular processes for the behaviour of intact animals. We plan to selectively interfere at distinct sites with the signalling pathways of withdrawal LTP and assess if the induction of OIH can be prevented or if the expression of OIH can be reversed. We expect that this project will reveal novel insights into the cellular mechanisms of OIH and we hope that our results will open new avenues to combat pain and reducing unwanted side effects of opioid therapy .

Opioids are substance that act similar to morphine on opioid receptors and thereby exert diverse effects on the body. They are often used in patients for pain relief. Paradoxically opiods may trigger pain or pain hypersensitivity, rather than relieving pain when given for prolonged periods of time or when the application is terminated abruptly rather than slowly. We have now discovered cellular mechanisms in the spinal cord and brain which may underlie opioid-induced pain hypersensitivity. The results of our studies were published in the journal Science (2009), The Journal of Neuroscience (2011, 2013 and 2015) and in Pain (2013). We found that abrupt but not tapered withdrawal from opioids leads to a long-lasting increase in the transfer of pain-related information between nerve cells in the spinal cord. As a consequence, normally harmless stimuli now exert strong excitation in pain-relevant pathways and may ultimately trigger strong pain sensations. This may be of particular importance in patients that underwent surgical procedures and who received opioids for pain relieve. This amplifying mechanism was demonstrable both, in the petri dish as well as in vivo. With high-tech microscopic techniques we were able to demonstrate that rise in intracellular calcium ion concentration in spinal neurons triggers a cascade of events that culminate in enhanced sensitivity to painful stimuli. All this could be prevented if opioid application was not terminated abruptly but slowly or if a special type of receptor for a neurotransmitter, the NMDA receptor, was blocked in the spinal cord. These findings may help preventing pain hypersensitivity when terminating an opioid therapy.All opioids are not alike. They rather differ substantially in their properties as well as in the mechanisms underlying their actions. We found that morphine and DAMGO induced signal amplification upon withdrawal as described above. In contrast, buprenorphine, a widely used opioid for pain relief, activated a completely different mechanism. At extremely low doses buprenorphine activated neurons in the brain that projected all the way down to the spinal cord. These neurons released a substance (serotonin) in the spinal cord that by acting on one of its receptors (the so-called 5-HT-receptor) facilitated pain-related excitation. This mechanism may only become relevant when buprenorphine concentration falls to very low levels. In summary, our study revealed distinct mechanism by which the different opioids may exert paradoxical pain hypersensitivity. These mechanisms were locally distinct from the sites where opioids depress pain-related events in the central nervous systems. This raises hopes that in the future novel pain treatments can be developed that fully preserve the desired effects of opioids without concomitant unwanted effects.