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.
Comments
Lars Arendt-Nielsen, Aalborg University
Use-dependent long-term
Use-dependent long-term potentiation (LTP) of synaptic strength between primary afferent neurons and second-order neurons can be induced in animals as well as humans (1) and be pharmacologically modulated (2). Various pre- and post-stimulation pharmacological interventions (including morphine) have been introduced to interact with LTP (3).
The current study showed that opioids reduced the established manifestation of LTP. A previous study showed less effect of spinally administrated morphine in LTP rats versus normal rats when the morphine was delivered two hours after the LTP induction (4). Another study showed that LTP is also induced by abrupt opioid withdrawal (5). The present study used brief applications of the opioid remifentanil, but in human studies, this administration regime has been shown to induce potent withdrawal hyperalgesia (6). As such, there are many complicated factors to take into consideration when the authors talk about erasing the spinal traces of pain. Pain is a multisensorial personal perception in patients, whereas the phenomenon they studied was neuronal field potentials from spinal nociceptive responding neurons under experimental conditions in rats.
Despite these limitations, it is of clinical interest to understand the different mechanism of action of opioids on the spinal sensitization processes, as they can either dampen or facilitate pain.
As opioids are different with respect to their ability to dampen spinal hyperalgesia, induce withdrawal hyperalgesia, and cause development of opioid tolerance, it would, in the future, be interesting to compare various opioids and study their short- and long-term effects on established LTP.
As LTP seems to have a negative impact on the pain system, long-term depression (LTD; also induced by conditioning stimulation) is helping dampen pain at the spinal level (7), and more studies are needed to understand also the differentiated effect of opioids (e.g., low doses) on this process, as LTP and LTD share common properties.
References:
1. Klein T, Magerl W, Hopf HC, Sandkühler J, Treede RD: Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans. J Neurosci 2004, 24:964-971.
2. Klein T, Magerl W, Nickel U, Hopf H-C, Sandkühler J, Treede RD: Effects of the NMDA-receptor antagonist ketamine on perceptual correlates of long-term potentiation within the nociceptive system. Neuropharmacology 2007, 52:655-661.
3. Ruscheweyh R, Wilder-Smith O, Drdla R, Liu XG, Sandkühler J. Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Mol Pain. 2011 Mar 28;7:20.
4.Buesa I, Urrutia A, Bilbao J, Aguilera L, Zimmermann M, Azkue JJ. Non-linear morphine-induced depression of spinal excitation following long-term potentiation of C fibre-evoked spinal field potentials. Eur J Pain. 2008 Aug;12(6):814-7.
5. Drdla R, Gassner M, Gingl E, Sandkühler J: Induction of synaptic long-term potentiation after opioid withdrawal. Science 2009, 325:207-210.
6. Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain. 2003 Nov;106(1-2):49-57.
7. Ellrich J. Long-term depression of orofacial somatosensory processing. Suppl Clin Neurophysiol 2006:58:195-208.
Ted Price, University of Arizona
While there is a whole body
While there is a whole body of literature on 7-transmembrane receptor (7TMR) activation and its role in either inducing (e.g., the case of some metabotropic glutamate receptors) or modulating the threshold for long-term potentiation (LTP; e.g., dopamine receptor D1 agonists), relatively little is known about the potential role of 7-TMRs in reversing established LTP. Since LTP has emerged as a potential cellular model for hyperalgesia in the dorsal spinal cord, the present findings concerning opioid receptor-mediated reversal of spinal LTP have far-reaching consequences for understanding the role of LTP in pain processing. They also are potentially important for researchers studying LTP in other neuronal circuits, as a single high-dose opioid treatment may be sufficient to reverse established LTP in other areas of the central nervous system.
In my view, one of the most interesting aspects of this new work from Sandkühler’s lab is its potential for immediate translatability into clinical trials and/or experimental human work. Insofar as the capsaicin model, used in rats in the present study, is also widely utilized in human biophysical and imaging experiments, a brief infusion of high-dose opioids in humans using this model may yield significant insight into the role of LTP in human pain perception. For instance, while a decrease in mechanical hyperalgesia was clearly observed in rats following the opioid infusion, it is difficult to know if the proposed reversal of potentiation also influenced ongoing pain or affective components of the pain state induced by the initial capsaicin injection. These questions are immediately addressable in human studies (that might also include functional imaging), and they have the potential to greatly enhance our understanding of the ramifications of spinal LTP for pain perception. Perhaps more importantly, these findings, for the first time, give clinical pain researchers a pharmacological tool (which is widely available and approved for human use) to potentially reverse a chronic pain state through the erasure of a “spinal memory trace of pain.” It will be very interesting to see what such studies reveal about the nature of LTP in chronic pain conditions, as this has long been an area of conjecture with little experimental evidence based on the lack of available tools for use in humans.
Mechanistically, the author’s findings suggest that opioid administration leads to an influx of calcium and activation of protein kinase C (PKC) and phosphatases that lead to a depotentiation via alterations in the phosphorylation status of AMPA receptors. These findings are consistent with a standard model of LTP induction; however, the authors find that inhibition of the atypical PKC PKMzeta does not lead to a reversal of low-frequency stimulation (LFS)-induced LTP. Insofar as myristolated-ZIP is a cell permeable and highly efficacious inhibitor of PKMzeta, and that myristolated-ZIP reverses established LTP throughout the central nervous system, these findings suggest that spinal LFS-induced LTP is molecularly distinct from LTP in other brain regions. Having said that, the present evidence is hard to rectify with our previously published work (cited in the original article of Asiedu et al., 2011), data from Min Zhuo’s group showing that ZIP depresses spinal synaptic transmission (Li et al., 2010), and with two recent papers (Laferriere et al., 2011; Marchand et al., 2011), one of which demonstrates that spinal treatment with ZIP leads to a reversal of capsaicin-induced hyperalgesia and wide-dynamic range neuron hyperexcitability (which has never been linked—to my knowledge—to LFS-induced LTP).
Nevertheless, the work of Drdla-Schutting et al. is undoubtedly an exciting advance and opens up a variety of novel opportunities for translation into clinical research. Time will tell whether such studies will ultimately be feasible or effective in humans, but I, for one, look forward to learning more about the importance of spinal LTP for clinically relevant pain states based on these groundbreaking basic findings.
References:
Asiedu, M.N., Tillu, D.V., Melemedjian, O.K., Shy, A., Sanoja, R., Bodell, B., Ghosh, S., Porreca, F., and Price, T.J. (2011). Spinal protein kinase M zeta underlies the maintenance mechanism of persistent nociceptive sensitization. The Journal of neuroscience : the official journal of the Society for Neuroscience31, 6646-6653.
Laferriere, A., Pitcher, M.H., Haldane, A., Huang, Y., Cornea, V., Kumar, N., Sacktor, T.C., Cervero, F., and Coderre, T.J. (2011). PKMzeta is essential for spinal plasticity underlying the maintenance of persistent pain. Molecular Pain7, 99.
Li, X.Y., Ko, H.G., Chen, T., Descalzi, G., Koga, K., Wang, H., Kim, S.S., Shang, Y., Kwak, C., Park, S.W., et al. (2010). Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex. Science330, 1400-1404.
Marchand, F., D'Mello, R., Yip, P.K., Calvo, M., Muller, E., Pezet, S., Dickenson, A.H., and McMahon, S.B. (2011). Specific involvement of atypical PKCzeta/PKMzeta in spinal persistent nociceptive processing following peripheral inflammation in rat. Molecular Pain7, 86.
Min Zhuo, University of Toronto
Spinal dorsal horn synapses are the first synapses that convey peripheral injury information to the central nervous system. It has been known that injury triggers learning-like long-term potentiation (LTP) in these sensory synapses, although molecular signaling pathways regulating spinal LTP are still to be determined. This new article from Jurgen Sandkühler’s group provides new insights on chronic pain and spinal LTP. A brief high-dose of opioid (remifentanil) caused almost complete erasure of such spinal painful memory trace and hyperalgesia! Several key downstream proteins and receptors that contribute to the erasure of LTP were identified, including protein phosphatase 1 (PP1) and AMPA receptors. By contrast, naïve sensory synapses that are typically inhibited by opioids do not show a similar ‘erasing’ effect. This finding provides novel information for our understanding of distinct signaling pathways for physiological (acute) pain vs pathological (chronic) pain at the spinal synaptic level. Future human studies using the same paradigm will be critical to confirm the translation of this basic discovery, which was made using an animal model of pain. There are great needs of new medicines or new treatments for chronic pain in patients. From a basic science point of view, it will be interesting to see if such application may also apply to treat other brain diseases, since opioid receptors are widely distributed in central nervous system.
Li-Yen Mae Huang, University of Texas Medical Branch at Galveston
Low-frequency stimulation (LFS) of sciatic nerve fibers was found to induce long-term potentiation (LTP) of synaptic transmission between primary afferent fibers and spinal dorsal horn neurons. LTP is thought to play a role in producing chronic pain conditions. Recording C-fiber-evoked field potentials in laminae I and II of rat spinal cord dorsal horns in vivo, Sandkühler and colleagues showed that LFS-induced LTP was much reduced following a one-hour intravenous infusion of a high dose (450 µg/kg) of the short-acting mu-opioid receptor agonist remifentanil, a phenomenon they dubbed opioid-induced depotentiation (OID). When the remifentanil was given twice separated by 1hr, LTP was completely abolished. On the other hand, OID could not be evoked by a low dose of remifentanil (225 µg/kg). Like many novel observations, more questions than answers are raised by the study. For instance, is a short-acting opioid required for the production of OID? What is the dose-response relationship between remifentanil and OID? Is there a threshold dose of remifentanil for the induction of OID? The authors found that OID was not affected by a gradual withdrawal of remifentanil. Can OID be induced by a gradual increase of a high dose remifentanil? If not, what is the minimum rate of increase of remifentanil required for the OID induction? Why is OID production dependent on opioid dose? Do high concentrations of remifentanil evoke a different set of protein kinases or phosphatases for AMPA receptor phosphorylation or de-phosphorylation? A better understanding of the mechanisms of OID will help us determine its application to chronic pain management.