The “Toll” of Opioid-Induced Glial Activation: Improving the Clinical Efficacy of Opioids by Targeting Glia

Glial activation participates in the mediation of pain including neuropathic pain, due to release of neuroexcitatory, proinflammatory products. Glial activation is now known to occur in response to opioids as well. Opioid-induced glial activation opposes opioid analgesia and enhances opioid tolerance, dependence, reward and respiratory depression. Such effects can occur, not via classical opioid receptors, but rather via non-stereoselective activation of toll-like receptor 4 (TLR4), a recently recognized key glial receptor participating in neuropathic pain as well. This discovery identifies a means for separating the beneficial actions of opioids (opioid receptor mediated) from the unwanted side-effects (TLR4/glial mediated) by pharmacologically targeting TLR4. Such a drug should be a stand-alone therapeutic for treating neuropathic pain as well. Excitingly, with newly-established clinical trials of two glial modulators for treating neuropathic pain and improving the utility of opioids, translation from rats-to-humans now begins with the promise of improved clinical pain control.

Introduction

Normally, a painful stimulus is perceived via a chain of events beginning with the activation of “pain”-receptive sensory nerve fibers. The resultant action potentials relay information of potential or actual tissue injury to pain transmission neurons in the spinal cord dorsal horn. These, in turn, send the information to multiple sites within the brain where various aspects of the pain experience (sensation, analysis of meaning, emotional reactions, etc) are analyzed and responded to. However, pain processing is not a passive process but rather is under powerful modulatory control. Pain messages can be suppressed by drugs like morphine, relayed unaltered, or amplified under conditions such as chronic pain. When chronic pain develops as a result of peripheral nerve injury, for example, these conditions have typically been attributed to a variety of neuronal changes, including altered excitability of sensory neurons, alterations in which neurotransmitters are synthesized and released by various sensory neurons, alterations in pain transmission neuron excitability via multiple changes in receptor and ion channel functions, and so on [1].

Intriguingly, powerful modulatory control exists not only for pain, but also for an organism's responses to opioids, such as morphine. Opioids not only suppress pain, they also activate endogenous counter-regulatory mechanisms that, for example, actively oppose opioid-induced pain suppression, enhance analgesic tolerance wherein repeated opioids lose their ability to suppress pain, and enhance dependence wherein organisms require continued opioid exposure to stave off drug withdrawal. These modulatory controls have again been attributed to a variety if neuronal mechanisms, including release of endogenous anti-opioid peptides such as cholecystokinin, internalization and/or desensitization of opioid receptors, alterations in opioid receptor signaling cascades, and so on 2, 3.

While modulatory control systems regulating pain and opioid actions have been thought to involve separate mechanisms, the present paper will review recent evidence that suggests that these two phenomena are closely related and involve overlapping mechanisms. This development has been predicted from prior studies focused on the neuronal bases of chronic pain and opioid tolerance, where striking commonalities such as upregulation of NMDA function transcend what initially appeared to be quite different phenomena [4]. The present review will extend the commonalities between chronic pain and various opioid effects to include a non-neuronal component (glial cells, especially microglia and astrocytes) and a distinctly non-traditional mechanism, that being activation of the innate immune receptor expressed by glia, called toll like receptor 4 (TLR4).

Concepts of chronic pain and opioid actions have evolved in recent years with the realization that alterations in neuronal functions fail to capture all of the critical mechanisms involved. Recognition of a role for microglia and astrocytes in these processes first occurred for pain in the early 1990 s, but the involvement of glia in modulating opioid actions was not discovered until a decade later. Indeed, the growing recognition of striking similarities in mechanisms underlying chronic pain and opioid tolerance directly led to the discovery of glial involvement in modulating opioid actions. Since glia were so convincingly important in chronic pain, it became a natural question whether they regulated the actions of opioids as well.

The goals of this article are to explore how glial activation impacts both pain and opioid actions. Pain will be considered first, including how glial activation increases neuronal excitability and how glial activation occurs under conditions leading to chronic pain. Included in this latter topic will be a discussion of TLR4 as a key glial activation receptor for the initiation and maintenance of chronic pain via TLR4-induced release of neuroexcitatory products such as proinflammatory cytokines. TLR4 will also be discussed as having a unique role in regulating the actions of opioids, as opioids have now been found to activate TLR4 on glia, in addition to their classical actions occurring through neuronal opioid receptors. Glial activation by opioids is an important phenomenon to understand, as glial activation opposes opioid analgesia and enhances opioid tolerance, dependence, reward and other negative side effects such as respiratory depression. Lastly, the implications of such glial activation will be considered for drug development aimed at improving both clinical pain control and clinical efficacy of opioids.