Pain has long been considered a neurological function which serves as a survival purpose under normal circumstances by protecting the individual from further danger. But when pain goes wrong and becomes chronic it no longer serves a relevant function. About ~one-sixth of the world population is afflicted with a form of chronic pain (1). Neuropathic pain, a form of chronic pain, can arise from trauma, inflammation, or infection but just how it occurs remains a dilemma. And how to treat such pain remains a huge problem; drugs such as anticonvulsants, opioids, gabapentin, and others that are thought to affect primarily neuronal activity fail in the great majority of patients (2).
As more studies were performed, it was realized that not only the nervous system was involved. Here is some of what is known about immune factors in this situation: active macrophages are recruited to the site of injury. Delaying macrophage recruitment to the site of injury also delays the development of neuropathic pain in animal models. Conversely, active attraction of macrophages enhances pain (3). The proinflammatory cytokines TNF, IL-1, and IL-6 seem to be key players.
Neuronally derived signals upon injury trigger the activation of glial cells (astrocytes and microglia). Once this happens, glia amplify pain by producing and releasing the above mentioned cytokines. These immune-derived factors increase at the site of trauma matching with the progression of pain. The effect of these immune-derived molecules ‘upset’ neurons making them more excitable. The more upset the neurons become, the more signaling molecules they release, and the more pro-inflammatory cytokines are released by glia—a vicious cycle. Treatment such as thalidomide, which decreases TNF, prevents neuropathic pain. This pain is also prevented in IL-6 knockout mice (4). But these treatments would be challenging in a clinical setting.
Why then do drugs such as opioids, that suppress neuronal activity, remain ineffective in long-term treatment of neuropathic pain? The answer involves the glial cells, especially microglia, which are releasing the inflammatory products. The evidence: first, treatment of neuropathic pain in animal models with an opioid and a reagent known to attenuate microglia activity (i.e., Minocycline or AV411: both in clinical trials) results in longer lasting pain relief with lower cytokine levels (5). This provided evidence that opioids were also acting on microglia; it was further shown that when opiates bind to microglial opiate receptors, more pro-inflammatory products are released.
Second, it is now known that neuronal opiate receptors are stereoselective and the microglia opioid receptors are not (6). This would suggest that it’s possible to separate the neuronal mediated pain suppressive opiate effects from the pain enhancing effects via microglia. Perhaps by a structural modification of opiates that prevents binding to the microglial receptor.
The take home message—prevention of opioid activation of microglia appears to be clinically relevant and has implications for understanding how pain states occur as well as how they may best be treated. While it is much more complicated than just this cell type and these immune mediators, it is certainly a new avenue to explore.
If you’re really interested in the topic, one of the forerunners in this field—Linda Watkins of CU Boulder—will be giving a seminar Wednesday, 10/24 at noon entitled “Curing chronic pain: New hope on the horizon”. It will be in the auditorium where IMMUNO 7630 is held.
1. Campbell et al. 2006. Neuron 52:77-92.
2. Finnerup et al. 2005. Pain 118:289-305.
3. Liu et al. 2000. Pain 86:25-32.
4. Cui et al. 2000. Pain 88:239-248.
5. Ledeboer et al. Pain 115:71-83.
6. Watkins et al. Brain Res Reviews in press
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6 comments:
This post is very interesting.
Can you tell me what opiod receptors microglia have?
In those studies do you know if they used only pure mu agonists or if they also tried mixed agonist/antagonists?
Thank you for this interesting blog, my father is in chronic pain and I will look further into this subject. I have a small question, in your research of this topic have you come across any TNF inhibitors or a compound called Naloxone? Naloxone is an antagonist for opioid receptors that have been shown in animal modeling to decrease cytokine and release of reactive species by microglia.
The opioid receptors on microgia are as yet unidentified. The indirect evidence is that neuronally inactive [+]-methodone upregulates mRNA for IL-1, IL-6 and TNF to at least the same degree as the neuronally active [-]-morphine and [-]-methodone upon IT injection. (Coats et al, Proc. Soc. Neurosci., in press).
The studies that attenuated microglial activity, like Minocycline, don't effect mu or opioid receptors that I'm aware of but dampen the response of microglia via other means (which isn't entirely known yet either).
The only TNF antagonist I've come across recently was the thalidomide that I mentioned. The other proinflammatory cytokine inhibitor mentioned in the review was lenalidomide but this doesn't cross the blood brain barrier so is not very effective in neuropathic pain yet is much more effective at decreasing TNF, IL-6, etc. (it is in other clinical trials for other pain conditions by Celgene).
Naloxone: right, I knew it was an opoid antagonist but hadn't come across decreased cytokine release by microglia. Thanks, I'll look into that.
Also FYI: according to L Watkins seminar, it appears that the microglia opiate receptors are probably stereoselective, just like on neurons. There seems to be another receptor (on which the patent will be released Nov 1) that microglia have that also just happens to bind both enantiomers of opiate. And the binding of the neuronally inactive form = less proinf cytokines.
Sweet...though with opioids won't tolerance/resistance come into play with chronic treatment? I know NSAIDs are anti-hyperalgesic; are they of any use in neurological pain? (i.e. is the pain "threshold" affected?) Can they even cross the BBB? Reminds me of a lecture I heard years ago, about a physiological basis for clinically depressed people being in pain: decreased sertonin levels decreased the the inhibition of a similiar cytokine-based pain biofeedback loop. Depressed people literally feel more pain from any given stimulus.
Yes Fritz, tolerance always does come into play with chronic opiate treatment. According to recent studies, there is compelling evidece that tolerance as well as withdrawl effects are largely mediated by microglia. Animal studies that treat subjects with morphine alone or with a microglia inhibitor = former case results in typical tolerance levels achieved and horrible withdrawls while the latter case doesn't develop near the tolerance or suffer much withdrawl. Seems to be linked with the microglial release of the proinflammatory IL-1, IL-6 and TNF. Can also see similar effects by treating with anti-inflammatory IL-10.
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