Activated Glia as Culprits in Opposing Opioid Analgesia & Driving Tolerance,

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One of the problems with the use of opiates for pain control is the development of analgesic tolerance and abstinence-associated pain enhancement. Classically every theory to explain such effects focused exclusively on neurons. New data demonstrate that glia are importantly involved as well.

It has been hypothesized, as early as 1988, that glial cells would logically be involved in morphine tolerance.  Given that (a) glia now appear to be intimately involved in the induction and maintenance of neuropathic pain, and (b) many parallels have been noted between mechanisms subserving neuropathic pain and morphine tolerance, this suggests that glia might also contribute to analgesic tolerance by creating a counter-regulatory response that dampens the efficacy of opiates. Glia can express mu, delta, & kappa opiate receptors, as well as orphan opiate receptor-1, implying that a broad array of opiates may exert direct actions on these cells. Indeed, exposure of astrocytes to either morphine or IL1 enhances the constitutive expression of mu opioid receptors by this glial population.  Similarly, exposure of astrocytes to a delta opioid agonist enhances the constitutive expression of delta opioid receptors by these cells.  Such data suggest that glia may potentially become increasingly responsive to opiates upon repeated administration.

Functionally, acute and chronic opioids stimulate glial production of nitric oxide, superoxide, TNF, IL1 and IL6, which are all known to excite pain pathways. Also intriguing are apparent parallels between drugs that suppress morphine tolerance and those that suppress glial function.  For example, the NMDA antagonists dextromethorphan and memantine each block morphine tolerance.  In addition to their actions on neurons, dextromethorphan inhibits microglial activation, and inhibits microglial production of TNF, nitric oxide, and superoxide in response to bacterial cell walls.  Memantine has likewise been reported to inhibit both astrocyte and microglial activation.  Such data suggest that the effects of NMDA antagonists on morphine tolerance may be due, in part, to suppressing glial activation by morphine. Thus, taken together, multiple lines of evidence suggest that morphine may activate glia and that this glial activation, in turn, may modulate the analgesic efficacy of morphine.

Glial activation in general, and glial IL1 in particular, (a) opposes acute morphine analgesia and (b) contributes to the development of morphine tolerance and the expression of abstinence associated pain facilitation. Systemic and intrathecal morphine increase mRNA and protein for proinflammatory cytokines in spinal cord, and enhance the release of IL1. IL1 antagonists, like disruption of glial activation, potentiate the analgesic effects of acute morphine, delay the development of morphine tolerance and reduce tolerance-associated pain facilitation.  Furthermore, the efficacy of morphine was enhanced in mice with genetically impaired IL1 signaling.  Conversely, administration of a low dose of IL1, while having no effects of its own on pain responsivity, abolishes morphine analgesia.
 
Notably, we have recently discovered that every clinically relevant class of opioids causes direct glial activation in a non-classical opioid receptor fashion, via opioid-induced activation of a member of the toll-like receptor (TLR) family, called TLR4. TLRs, as a family, recognize a diverse range of moieties or “patterns” on exogenous (e.g., lipopolysaccharide [LPS] of gram-negative bacteria such as E. coli and Salmonella) and endogenous (e.g., heat shock proteins and cell membrane components released from damaged cells) substances that are considered to be danger signals and hence warrant activation of the innate immune system aimed at defending the survival of the host. TLR4 has been extensively characterized, as it is the TLR that recognizes endotoxin (LPS). Binding of agonists to TLRs activates similar downstream intracellular signaling pathways to those previously documented for IL-1 binding to its cognate receptor, resulting in a powerful proinflammatory signal. Indeed, the striking similarity of these pathways is reflected by it being called the TLR/IL-1 signaling cascade.

Intriguingly, in addition to being activated by diverse opioids, TLR4 has also been demonstrated to be essential to neuropathic pain states. TLR4 knockouts and/or knockdowns suppress neuropathic pain. We have extended these findings to normal adult rats by demonstrating that acute intrathecal administration of a selective TLR4 antagonist suppresses well-established neuropathic pain induced by chronic constriction injury, in addition to enhancing opioid analgesia.  Such data demonstrate ongoing stimulation of TLR4 under conditions of neuropathic pain.
 
From above, it is clear that there is potentially great application for a blood brain barrier permeable small molecule that could block TLR4, as it appears that TLR4 may lie at the intersection between neuropathic pain and opioid-induced glial activation. Based on scattered hints in the literature, we have discovered such a drug.  We have discovered that opioid agonists activate TLR4 and opioid antagonists non-stereoselectively block TLR4 activation. Thus, the exciting potential exists that (+)-opioid antagonists (which have no effect on neuronal opioid receptors that only bind (-)-opioid isomers) may be uniquely positioned to simultaneously suppress neuropathic pain, suppress opioid-induced glial activation, and yet not compromise the pain-suppressive effects of opioids agonists on neurons.
 
As an alternative approach to simultaneously treat neuropathic pain and enhance the efficacy of opioids, we have been exploring the effects of AV411 (ibudilast), an orally active, blood brain barrier permeable glial activation inhibitor with excellent CNS penetrance.  Notably AV411 is currently in Phase II clinical trials for the treatment of neuropathic pain at the University of Adelaide and soon to enter clinical trials in the U.S. for this indication as well.  In collaboration with Avigen, we have explored the effect of this glial modulator on opioid actions and have documented that systemic AV411: enhances acute morphine and oxycodone analgesia, delays opioid tolerance, suppresses the development of morphine and oxycodone dependence/withdrawal, and suppresses opioid reward as measured both neurochemically & behaviorally.
 
Taken together, the data are now compelling that opioid induced glial activation powerfully dysregulates the actions of opioids and that the development of glial modulators promise to treat not only neuropathic pain but enhance the clinical utility of opioid analgesics as well.

Suggested Reading: 

Hutchinson, M.R., Bland, S.T., Johnson, K.W., Rice, K.C., Maier, S.F. & Watkins, L.R., Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward, TheScientificWorldJOURNAL 7 (2007) 98-111.

Watkins, L.R.,  Hutchinson, M.R., Milligan, E.D. & Maier, S.F., “Listening” and “talking” to neurons: implications of immune activation for clinical pain control and increasing the efficacy of opioids, Brain Research Reviews, 56 (2007) 148-169.

Ledeboer, A., Hutchinson, M.R., Watkins, L.R. & Johnson, K.W., AV411 (ibudilast): a new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes, Expert Opinion on Investigational Drugs,  16 (2007) 935-950.

Watkins, L.R., Hutchinson, M.R., Ledeboer, A., Wieseler-Frank, J., Milligan, E.D. & Maier, S.F., Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids, Brain, Behavior & Immunity, 21 (2007) 131-146.