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CME

Recent Findings in Neuronal Mechanisms Affecting Peripheral and Central Mechanisms of Pain

  • Authors: Frank Porreca, PhD
  • THIS ACTIVITY HAS EXPIRED
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Target Audience and Goal Statement

This activity is designed for healthcare professionals specializing in the treatment of pain.

Program Overview
This program is designed to provide a comprehensive review of the physiology of pain transduction, emphasizing receptor physiology and ionotropic mechanisms of pain modulation. The impact of exogenous opioids on the plasticity of synaptic receptors and channels will be discussed as it relates to the clinical sensitivity and tolerance to opioid therapy. The rationale for the use of different types of opioids, and for opioids of different durations of action, will be explained. Novel opioid delivery systems will be described and justified based on what is known about receptor and synaptic physiology and the etiology of the pain.

At the conclusion of this educational activity, participants should be able to:

  • Recognize the molecular mechanisms involved with analgesic opioid use in chronic pain therapy;
  • Identify emerging data in the development and understanding of the role and function of NMDA receptors in chronic pain;
  • Understand the mechanism and location of action of opioid pain medications;
  • Understand the various types of opioid delivery systems and the clinical indications for each.

 


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When individuals in a position to control content have reported financial relationships with one or more commercial interests, MediCom Worldwide, Inc. works with them to resolve such conflicts to ensure that the content presented is free of commercial bias. The content of this presentation was vetted by the following mechanisms and modified as required to meet this standard:

  • Content Peer Review by external topic Expert
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Off-Label/Investigational Disclosures
In accordance with MediCom Worldwide, Inc. policy, the audience is advised of the following disclosures regarding unlabeled or unapproved uses of drugs or devices:

At the time of printing, Dr. Inturrisi indicated that his presentation would include the discussion of unlabeled uses of d-methadone that are not approved by the FDA for certain uses in the United States. Dr. Inturrisi indicated that his presentation would not include the discussion of products that have not been approved by the FDA for any use in the United States at the time of printing.

At the time of printing, Dr. Pasternak, Dr. Porreca, and Dr. Rowbotham indicated that their presentations would not include the discussion of unlabeled uses of commercial products or investigational products not yet approved by the FDA for any use in the United States.


Author(s)

  • Frank Porreca, PhD

    Professor of Pharmacology and Anesthesiology; Director, Theme for Medical Neuroscience, University of Arizona, Tucson, Arizona

    Disclosures

    Disclosure: Dr. Frank Porreca ha disclosed that he has no significant relationships with the grantor Cephalon, Inc. or any other commercial company whose products and services may be related to his presentation.


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CME

Recent Findings in Neuronal Mechanisms Affecting Peripheral and Central Mechanisms of Pain

Authors: Frank Porreca, PhDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

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  • I want to begin by telling you about how we got interested in these particular unusual neurobiological actions of opioids. In our laboratory, we study mechanisms of chronic pain and we emphasize evaluation of sensory thresholds in animals and, in particular, the lowered sensory thresholds that exist after we produce a variety of manipulations to produce experimental neuropathic pain or inflammatory pain, visceral pain, bone cancer pain, etc. In the course of these studies, we evaluate molecules that have potential novel mechanisms of action to see if those molecules can bring those sensory thresholds back to normal levels. Of course, one of our tasks is to determine how they compare with reference molecules. Specifically, the reference molecules, of course, are the ones very clinically important for the treatment of pain: the nonsteroidal anti-inflammatory drugs (NSAIDs), and the opioids.

    When we give opioids and we look at sensory thresholds in animals what we are expecting to see is that sensory thresholds will be increased following activation of opioid receptors, as Dr. Pasternak just told you. These are inhibitory receptors. They hyperpolarize neurons. They inhibit the influx of calcium in the nerve terminals, prevent the release of excitatory transmitters, and actually produce the analgesic mechanism or the analgesic actions that we are all interested in and which we exploit clinically. But, what we saw when we gave these opioids in our models of pain is that under many different conditions, especially in conditions in which we gave opioids chronically, is that we did not see an elevation of sensory thresholds. In fact, we saw a reduction of sensory thresholds, indicating that under some conditions, particularly conditions in which we gave opioids over some extended period of time that we saw an excitatory action of the opioid, or a hyperalgesic action of theopioid. We were quite interested in knowing what the mechanism of this hyperalgesia was, and we thought it was relevant or potentially relevant from the clinical perspective for a number of reasons. The first is that opioids, of course, are second in prescriptions to NSAIDs for the control of pain. Opioids are increasingly being used for the treatment of chronic pain and, of course, opioids are the mainstay for the treatment of cancer pain. So, our decision to study the mechanism of opioid-induced hyperalgesia seemed to be relevant also because in the literature there were many reports from physicians that had been treating their patients, anecdotal reports, where they observed what we might refered to as a paradoxical pain or hyperalgesic effect of the opioids. The observations of hyperalgesia produced in animals were from many different laboratories around the world and physicians would write about the unusual hyperalgesic actions of opioids that were seen in patients. Thedescriptions seem to go along this line, ie, "that the hyperalgesia that was produced was noted in the areas of the body that were quite distinct from the site of the original pain complaint and it was relevant to the dose of the opioid that was used. By diminishing the dose of the opioid, the hyperalgesic effect went away."

    Walter Ling, Peggy Compton, and colleagues at UCLA report that methadone maintenance patients are hyperalgesic when tested using a variety of different stimulus modalities. So, it seems that the phenomenon can be demonstrated both in animals and in man. Now, the concept that emerged from these studies is that the hyperalgesia that is produced is concurrently expressed with the analgesic actions of the opioids. So, the way that we could think about it is that within the analgesic action of an opioid, there is buried a hyperalgesic component, and we can distinguish the analgesic action from the hyperalgesic action on the basis of the mechanism and on the basis of the time course. If we could conceive of blocking the hyperalgesic effect during that period of analgesia, we would see more analgesia and that, of course, is the concept behind the exploration of combination therapy such as mu-opioids and NMDA antagonists. What we know is that the time courses of these effects are differentas well. Once the analgesic action of the opioid is diminished, the hyperalgesic action emerges, and shows a longer lasting effect. We now also know that the hyperalgesia that we see, at least in animals, is an evoked hyperalgesia. It is elicited by both high-intensity and low-intensity stimuli and so we can use words such as allodynia and hyperalgesia to describe those effects. The mechanisms of opioid-induced hyperalgesia are unknown and that is exactly what we want to explore.

    In the preclinical laboratory, what we are doing is taking rats and implanting osmotic mini-pumps that deliver either saline or morphine. The morphine dose is at a submaximal dose. These were not very high doses of morphine. I am going to talk to you about morphine today, but we have used the variety of different molecules to show that this is a receptor-mediated event and is not dependent upon specific metabolites of morphine. What you see is if you go ahead and evaluate sensory thresholds after administration of saline or morphine 6 hours after implantation of the mini-pump, is that when you apply a noxious radiant heat stimulus, the threshold for response is increased. This is, of course, the inhibitory action of the opioid, the analgesic action of the opioid that we wish to exploit from the clinical perspective. This is analgesia in a noxious radiant heat stimulus, analgesia in a noxious mechanical stimulus.

    Now we change the time scale from a period of hours from the 6-hour time point shown here to a period of days, then things change dramatically. What we see if we apply a radiant heat stimulus is that over a period of several days; 3 days, 4 days, 5 days; that the sensory thresholds do not increase, but, in fact, they decrease. So, we start to see a sustained thermal hyperalgesia, a sustained noxious mechanical hyperalgesia. And if we use Von Frey filaments, which are these light calibrated filaments, and apply them either to the paw of the rat or to the face of the rat, you see that the response thresholds to a light tactile stimulus decreases as well and so, we see a tactile allodynia that can be expressed at all parts of the body. The nervous system has now changed in response to these various stimuli and is changed as a consequence of administration of morphine. What we wanted to know is what was happening that was going to underlie these effects that we saw in terms of sensorythresholds and we did not, of course, want to re-invent the wheel. We wanted to look for parallels with injury into states of hyperalgesia.

    The questions that we were asking included were they mechanistic parallels with injury-induced pain states such as inflammatory pain states or neuropathic pain states? Was there a sensitization of peripheral nociceptors? Was there a central sensitization? But the caveat here is: were these things happening in the absence of tissue injury? Was there an engagement of descending pain facilitation arising from the brainstem from the rostral ventromedial medulla, again without tissue injury?

    The reason that we thought that these were potentially important things for us to evaluate is that when we look at the types of patients that suffer from pain, there are many examples of individuals who suffer pain without prominent tissue injury, and these might include patients that suffer from fibromyalgia, patients who have irritable bowel syndrome (IBS), complex regional pain syndrome (CRPS) type 1, and perhaps even patients who are suffering from migraine. So, we wanted to explore those mechanisms. I do not have time today to tell you about the processes of peripheral sensitization. I really want to talk to you about a system that is important in modulating the flow of noxious traffic. This is a modulation of noxious input arising from cells in the rostral ventromedial medulla.

  • Slide 2.

    Slide 2.

    (Enlarge Slide)
  • This is a slide that represents a circuit diagram redrawn from work by Howard Fields and colleagues many, many years ago where he identified specific cells in the rostral ventromedial medulla that project from the rostral ventromedial medulla to the dorsal horn of the spinal cord. The output from these cells can either positively or negatively modulate the flow of noxious traffic from the primary afferent fibers. The descending pain inhibitory cells, Dr. Fields called OFF cells, these cells when activated by conditions of stress or when engaged by administration of opioids (through disinhibition), can produce very significant analgesic actions. Now, also in the rostral ventromedial medulla are these other cells; these cells were called ON cells or pain facilitation cells that we know less about in terms of their mechanism. But, what is important is that when these cells are activated, the flow of noxious information is actually facilitated or enhanced. So, these descending painfacilitation cells might play an important role in pain and you could conceptualize it this way: If those descending pain facilitation cells are overactive or increasingly active then this really represents a mechanism of chronic pain. We did a series of experiments to test that hypothesis and to test the idea that increased descending facilitation from the rostral ventromedial medulla might be important in mediating this phenomenon of opioid-induced hyperalgesia.

    I do not show you all the data here, but I summarize the concepts this way: If we inactivate the cells in the rostral ventromedial medulla by microinjecting lidocaine to silence the activity of neurons in that area, we block opioid-induced hyperalgesia. If we lesion the dorsolateral funiculus, the pathway by which these cells project to the dorsal horn of the spinal cord, we block the opioid-induced hyperalgesia. If we use a ribosome inhibitor that gains entry into these specific cells by way of a saporin construct, again we block opioid-induced hyperalgesia. We show that engaging this descending pathway is critical for the expression of the hyperalgesic actions of the opioids.

  • Slide 3.

    Slide 3.

    (Enlarge Slide)
  • We ask questions such as what might drive the descending pain facilitation mechanism.

    We were able to measure upregulation of cholecystokinin in the rostral ventromedial medulla after administration of the opioid. Cholecystokinin (CCK) is hyperalgesic. The hyperalgesia produced by opioids is blocked by CCK 2 receptor antagonist. Upregulation of CCK may be important in driving the descending facilitation. The reason that was particularly interesting to us is that there were changes that we can measure in the dorsal horn of the spinal cord after administration of opioids and many of these seem to be secondary to the activation of the descending pain facilitation mechanism. Thus, when we upregulate CCK in the rostral ventromedial medulla, we drive the descending pain facilitation mechanism, we start to see changes in the dorsal horn of the spinal cord.

  • Slide 4.

    Slide 4.

    (Enlarge Slide)
  • Following the administration of opioids, we see upregulation of excitatory transmitters such as substance P and calcitonin gene related peptide (CGRP) in cells in the dorsal root ganglion. When we evoke the release of these excitatory transmitters with some stimulus, capsaicin or heat stimulus, we see an enhanced evoked release of those transmitters. That enhanced evoked release depends on the expression of a peptide called dynorphin, which is upregulated after opioid treatment. Its upregulation is prevented by lesions of the dorsolateral funiculus, indicating that the plasticity that was seen in the upregulation of dynorphin is dependent upon the activation of the descending pain facilitation system. So, dynorphin is particularly important because it seems to act in an excitatory fashion. When we administer dynorphin, we can enhance the evoked release of these excitatory transmitters. In some work that we did with Dr. Tony Yaksh and colleagues, we found that if we administereddynorphin into a normal animal, we could enhance the release of excitatory mineral acids. We could enhance the releases of prostaglandin E2 and prostaglandin, of course, can sensitize primary afferent nociceptors. Dynorphin can activate and enhance the transmission of pain by acting postsynaptically as well.

    It seemed, therefore, that the story with dynorphin seemed to be quite solid because the hyperalgesia produced by opioids was depended upon the expression of dynorphin.

    If we administer an antiserum to dynorphin or MK801 to block NMDA receptors, we block that hyperalgesia. If we use prodynorphin knockout mice that do not make dynorphin, the wild-type mice develop a tactile hypersensitivity, the thermal hypersensitivity, and the prodynorphin knockout mice do not. So, the opioid-induced hyperalgesia is dependent upon the activation of a descending pain facilitation system. It drives plasticity in the dorsal horn of the spinal cord, to upregulate dynorphin. Dynorphin is excitatory and that, of course, is validated in a number of ways. This is evoked release of CGRP from embryonic dorsal root ganglion cells. This is enhanced evoked release of CGRP from slices of dorsal of the spinal cord. If we microinject or we give intrathecal administration of non-opioid fragments of dynorphin, there is tactile hypersensitivity and thermal hypersensitivity, very much reminiscent of what we see when we just gave opioids. So, dynorphin seems to have a criticalrole.

    Now, of course, the issue with the dynorphin is that you probably recognize it as an opioid peptide and dynorphin is an opioid peptide. It is 17 amino acid peptide cleaved from precursors. You can see at the N terminus that it has a five amino acid sequence beginning with an N terminal tyrosine. This is the sequence of leucine enkephalin. Now, when we do receptor-binding studies with dynorphin, we find that it binds at nanomolar concentrations to kappa opioid receptors to mu-opioid receptors. When we cleave the N-terminal tyrosine it loses its affinity for opioid receptors. But, that does not mean that it is inactive. In fact, the des-tyrosine fragments of dynorphin are completely active. They are just excitatory in nature. So, what we have is a situation with a single peptide dynorphin, which we recognize as an opioid peptide. It binds to mu and kappa opioid receptors. It produces an inhibitory effect as we expect from all opioids to diminish antinociceptive tone, to reduce pain.

  • Slide 5.

    Slide 5.

    (Enlarge Slide)
  • But what we see is that under circumstances dynorphin is upregulated so that it has a non-opioid action, presumably acting through specific, non-opioid, receptors.

    The question, of course, is which receptors? It produces excitatory effects promoting allodynia, promoting hyperalgesia, and enhancing pain. So, the big question is which receptors?

    Without the time to take you through the details, I will tell you the approach that we took. We took cells in culture, dorsal root ganglion cells and culture, we began a screening program in which we looked at the effects of the des-Tyr dynorphin to promote calcium influx into the cells and then we simply screened for antagonist and asked what blocks this excitatory effect of dynorphin. We looked at more than 50 different compounds. What we found is that dynorphin which stimulates calcium influx through voltage gain in calcium channels, through L and P type calcium channels, PQ-type calcium channels and this effect was blocked surprisingly by bradykinin receptor antagonist and that was the real surprise. So, we then were able to confirm that dynorphin can bind to bradykinin receptors, an unexpected binding site for what we considered to be an opioid peptide and that dynorphin-induced hyperalgesia was blocked by bradykinin receptor antagonist. Here is an experiment that summarizesthis very quickly: In bradykinin B2 receptor knockout mice, when we give dynorphin by the intrathecal route, the wild-type mice show the tactile, the thermal hypersensitivity that we expect, the bradykinin B2 receptor knockout mice do not. This indicates that bradykinin is central to how dynorphin produces these hyperalgesic actions.

    Now, the question you might be asking is what about bradykinin itself? That is a substance that is produced and released as a consequence of injury. Bradykinin is not a neurotransmitter. It is released and produced by cleavage of precursors in the blood. So, high-molecular-weight kininogens and low-molecular weight kininogens can be cleaved to produce bradykinin or other bradykinin-like peptides that can act at the constitutively expressed bradykinin B2 receptor or the inducible bradykinin B1 receptor and bradykinin is extremely labile. When we administer bradykinin intrathecally we do not see any changes in sensory thresholds. It is broken down too quickly. So, the concept that emerges is that dynorphin is upregulated and can act at bradykinin receptors to promote hyperalgesia.

  • Slide 6.

    Slide 6.

    (Enlarge Slide)
  • We can think about the story in the periphery. We can imagine tissue injury occurring, the production of bradykinin taking place, the binding of bradykinin to bradykinin receptors, signaling through a GQ pathway to induce PKC phosphorylation of sensory transducers, such as the TRPV1 1 channel, promoting the influx of calcium into the neuron, and leading to a state of sensitization. But, in the spinal cord, we do not have bradykinin. What happens when we have dynorphin is that it probably binds the opioid receptors to produce a very weak analgesic action, perhaps, by inhibiting calcium influx through N-type calcium channels.

  • Slide 7.

    Slide 7.

    (Enlarge Slide)
  • Now, in the setting of chronic opioids, we have upregulation of dynorphin. Dynorphin in the spinal cord can act at bradykinin receptors to again activate L- and PQ-type calcium channels to result the influx of calcium to underline this phenomenon of opioid-induced hyperalgesia. This hyperalgesic action would overwhelm any minor analgesic action produced by the dynorphin.

  • Slide 8.

    Slide 8.

    (Enlarge Slide)
  • What I have said is that opioids produced plasticity in the rostral ventromedial medulla that activates at a secondary level, the expression of dynorphin in the dorsal mode of the spinal cord. Dynorphin is excitatory. It can act to bradykinin receptors to enhance the transmission of the pain signal and to produce the hyperalgesic action.

    Now, why are we interested in this? What is the potential in importance of this? First of all, I am telling you that opioids can, under some circumstances, produce neuroplastic changes, which mimic inflammatory pain and that is certainly what we intend to do when we administered opioids. That is a little bit disturbing. The second thing is that opioids produce neuroplastic adaptations, and these may have clinical implications in the sense that they may produce unexpected hyperalgesia and unexpected allodynia. If we think about that, hyperalgesia and allodynia are really examples of increased pain with any given stimulus and pain can be thought of as a physiological antagonist of analgesia. So, increased pain may require more pain reliever and so that could play a role in the expression of opioid tolerance. The third thing is that these changes persist for very long periods of time after exposure to the opioid. I want to give you just one example of this. One more little piece ofdata we performed in collaboration with Dr. Cyril Rivat where we infused either saline or morphine using an osmotic mini-pump for 7 days. Then we allowed the sensory thresholds of the animal to recover to normal and then the experiment is carried out on day 69. A long, long time after exposure to the opioids, we produce an incision of the hind paw, using the model developed by Tim Brennan. We look at the hyperalgesia that results and we evaluate the time it takes to recover. You can see that the animals that were pre-exposed to saline recover at this rate. The animals that had received morphine some 70 days ago take much longer to recover. The effect persists for extremely long periods of time and with unexpected result.

    The other bit of information is that if we evaluate these hyperalgesic actions of opioids on a background of pain and here, I am using a model of bone cancer pain, osteolytic sarcoma-induced bone cancer, a model that was developed by Drs. Prisca Honore and Pat Mantyh. The sarcoma cells are implanted into the femur of the mouse. They are sealed, and they produce pain. The hyperalgesia is produced by the opioid. When you add the opioid to the cancer pain, you see that the pain is not actually relieved, it is enhanced. You look at the spontaneous pain that occurs, the flinching behavior. You see, the flinching is enhanced by the presence of opioids and you can see that the guarding behavior is enhanced by the presence of opioids. Now, of course, we can overcome this pain by simply giving higher bolus doses of the opioid. That is readily achievable, but when we give the opioid as a background, we are not relieving the pain. We are actually enhancing the pain, and the surprising findinghere is that the sarcoma cells will produce bone destruction. If we add morphine, the bone destruction actually increases. I am just illustrating this to you qualitatively. We have quantified this as well. When looking at the numbers of spontaneous fractures that occur in animals receiving only the sarcoma cells or animals receiving the sarcoma cells on a background of opioids, the rate of spontaneous fracture basically doubles in the presence of the opioid.

    Whether this applies to all cancer pain states, of course, we do not know. We do not know what the ultimate translational value of this is, but the important point to note is that these neuroplastic adaptations that we can measure in animals do raise the possibility that the hyperalgesic actions of the opioids can have some negative influence on the basis of the expression of pain.

    And with that, I would just like to end. Thank you for your attention and I thank my colleagues, especially Josephine Lai and Todd Vanderah, Michael Ossipov, Tamara King, and the rest of the people that worked with us the University of Arizona. Thank you very much for your attention.

  • Slide 9.

    Slide 9.

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