A single, high dose of opioids might be able to cut off chronic pain at the roots. That is the hope offered by a study published in the January 13 issue of Science. The experience of pain strengthens synapses in the spinal cord, creating exaggerated responsiveness to subsequent sensory inputs. Jürgen Sandkühler and colleagues at the Medical University of Vienna, Austria, found that, in rats with this kind of pain hypersensitivity, an unusually high dose of the opioid remifentanil had a novel effect: It reversed the sensitization and produced a lasting decrease in pain. If the results extend to humans, it could mean durable relief for patients with some forms of chronic pain.
Neuronal activity can fortify synapses in the nervous system by the process of long-term potentiation (LTP). In the hippocampus, LTP stores memories. In the spinal cord, it forms the “memory” of painful input that is thought to propel a wide variety of chronic pain conditions. The mechanism involves changes in spinal neurons that make them hyper-responsive to signals from primary afferents, a phenomenon also called central sensitization (for reviews, see Latremoliere and Woolf, 2009; Woolf, 2011; and Sandkühler and Gruber-Schoffnegger, 2011).
In spinal LTP, an incoming barrage of glutamate from nociceptive neurons causes post-synaptic neurons in the dorsal horn to experience a large influx of calcium ions through NMDA-type glutamate receptors. That, in turn, activates calcium-dependent kinases and phosphatases, which modify AMPA-type glutamate receptors, rendering the channels—and the neurons—more responsive to subsequent glutamate release. Thus, pain sets up a vicious cycle, which makes future stimuli hurt more.
It is possible to temporarily mollify this pain-inducing process: Continuous administration of opioids, for example, can inhibit the release of neurotransmitters from primary afferent neurons, dampening incoming pain signals. But actually reversing synaptic potentiation has been elusive. “As soon as you turn off an infusion [of opioids], the inhibitory effect wanes away,” Sandkühler told PRF, such that patients in chronic pain are often tied to chronic opioid therapy.
In the new study, first author Ruth Drdla-Schutting and colleagues induced LTP in spinal synapses in rats by electrically stimulating sciatic C-fibers. They then treated the rats with an unusually high dose of the ultra-short-acting opioid remifentanil (450 μg/kg, administered intravenously for one hour) and measured C-fiber–evoked activity in the potentiated synapses in the dorsal horn. The researchers saw that, during infusion, remifentanil depressed synaptic activity, as expected. But when they stopped the infusion, rather than rebounding, the activity stayed low, close to pre-LTP levels. After a second high dose of remifentanil, the potentiation appeared to be reversed completely.
Experiments with a μ-opioid receptor (MOR) antagonist indicated that spinal MORs were required for the effect. Calcium signaling was involved, too, because an NMDA receptor antagonist, which blocks Ca2+ entry, inhibited the remifentanil-induced depotentiation, as did a blocker of the ryanodine receptor, which gates intracellular Ca2+ stores. The researchers also found that remifentanil returned AMPA receptors to their basal phosphorylation states. Paradoxically, protein kinase C (PKC) and protein phosphatase 1 (PP1)—enzymes that alter AMPA receptor phosphorylation to increase channel conductance during synaptic potentiation—were also required for the remifentanil-induced reversal.
In most experiments in the study, LTP was induced by low-frequency electrical stimulation. However, the researchers also found that when they induced LTP in other ways, including high-frequency electrical pulses, or subcutaneous injection of capsaicin, high-dose remifentanil was again able to reverse the potentiation.
Importantly, the treatment had an effect not only on electrical activity from spinal synapses, but also on animals’ behavior. High-dose remifentanil partially relieved capsaicin-induced mechanical hyperalgesia for three hours after treatment.
It remains to be seen if high-dose opioids could have a similar effect in people. Even if they do, such a treatment certainly would not be a quick and easy solution for discomfort. Doses of the sort used in this study, Sandkühler said, are rarely used except in opioid-tolerant patients; in other patients, they could cause respiratory failure. That means a high-dose treatment could be administered only under the careful supervision of an anesthesiologist. But for some patients with intractable chronic pain, existing treatments bring their own risks, and only temporary, unsatisfactory relief. Sandkühler told PRF that he and clinical colleagues have started recruiting patients to see whether a high-dose treatment could help.
An important consideration, Sandkühler noted, is that while treatment with high-dose opioids may normalize potentiated synapses, his group showed in an earlier study that it actually induces LTP in naïve synapses when the drug is withdrawn abruptly (Drdla et al., 2009). Thus, in patients with chronic pain, high-dose opioid treatment runs the risk of relieving painful signaling at some synapses, but producing it in others. It should be possible to separate these effects, he said, using a tapered withdrawal regimen.
Sandkühler thinks that the new findings, if they do extend to people, might offer a diagnostic tool for central drivers in pain. If high-dose opioid treatment significantly reduced patients' pain, “then you could conclude that LTP is a major cause for their pain,” Sandkühler said. “So it could be used as a distinguishing factor—for finding out which mechanisms underlie a given patient’s pain problem.”
A host of questions remain, including how long the effect lasts—do high-dose opioids reverse central sensitization permanently, or just for a short time? Sandkühler said he also wants to know whether the normalizing effect of high-dose remifentanil can be achieved with other opioids, and whether it occurs in other synapses, including Aδ-fiber nociceptive synapses in the dorsal horn.
Image and video credit: J. Sandkühler, Medical University of Vienna, Austria.