Trends in Neurosciences
Glia: novel counter-regulators of opioid analgesia
Introduction
Analgesic tolerance develops upon repeated administration of opioids such as morphine, requiring increased dosage to maintain pain control. This is problematic because increases in opioid doses increase side-effects such as constipation or miosis [1]. Also, chronic administration of opioids leads to pain amplification upon drug discontinuance. Withdrawal-induced pain enhancement, like analgesic tolerance, is a clinically relevant problem [1].
At a conceptual level, opioid tolerance could be produced by various processes. Opioids relieve pain, in part, by binding opioid receptors on spinal cord pain-transmission neurons, thereby inhibiting neurons that relay pain messages to the brain. Thus, chronic administration of opioids could cause adaptation within opioid-receptor-expressing neurons, rendering opioid actions at those neurons less effective. For example, repeated opioid receptor activation might downregulate these receptors. Here, no other neurons are involved. Alternatively, repeated opioid administration could strengthen a system (or systems) outside the pain-transmission neurons that actively opposes opioid actions. Within such ‘opponent processes’ or ‘counter-regulatory influences’, there are two possibilities. One is that this process merely antagonizes the actions of opioids on pain-transmission neurons. This could involve the release of a substance that produces no neuronal excitation on its own but simply prevents opioid binding. The second possibility is that cells of a pain-facilitatory system release substances that activate and/or sensitize pain-transmission neurons, rather than simply antagonizing the direct effects of opioids. Work described in this review indicates that the CNS contains mechanisms that not only inhibit but also facilitate pain. Pain represents a summation of the effects of systems that facilitate and inhibit it; thus, opioid tolerance could be produced, at a behavioral level, by strengthening of pain-facilitatory systems by repeated opioid administration. These two types of counter-regulation can be distinguished by blocking the actions of the opioid at its receptor in subjects that have repeatedly received an opioid. In the case of simple antagonism, the organism would remain at baseline levels of pain; by contrast, if tolerance has occurred because there has been counter-facilitation, the individual would experience enhanced pain.
Many mechanisms have been postulated to account for opioid tolerance and withdrawal-induced pain enhancement. All implicate neuronal adaptations [1], such as: decoupling, internalization and/or downregulation of opioid receptors; upregulation of NMDA receptor function; downregulation of glutamate transporters; and production of nitric oxide [1]. These adaptations fit into the first category of tolerance mechanism. However, there is also support for a counter-regulatory system: release of anti-opioid neuromodulators such as cholecystokinin (CCK) [2] and dynorphin [3] has been proposed to oppose opioid function without influencing the pain neurons directly.
Despite decades of study, mechanisms underlying morphine tolerance and withdrawal-induced pain enhancement remain far from clear [1]. This review explores new evidence suggesting that non-neuronal cells called glia could be pivotal in counter-regulating acute morphine analgesia, in creating morphine tolerance and in opioid-withdrawal-induced pain enhancement.
It should be recognized that both microglia and astrocytes are implicated in pain modulation, as will be discussed later. In a minority of situations, the relative importance of microglia versus astrocytes is known and will be clarified. Because in most situations their relative roles are not yet clear, the term ‘glia’ will be used throughout this article to refer to both microglia and astrocytes.
The argument will be that: (i) glia are activated by opioids, (ii) glia are crucial to induction of pain facilitation that then summates with the analgesic impact of opioids, and (iii) glial activation by opioids strengthens with repeated opioid administration. These data predict that the clinical efficacy of morphine, and probably other opioids [4], could be enhanced by targeting these newly recognized, pain-facilitatory effects of glial activation.
Section snippets
Historical overview: glia as facilitators of pain
It was hypothesized as early as 1988 that glia would be involved in morphine tolerance [5]. This was based on the facts that protein synthesis appeared necessary for the development of opioid tolerance and that protein synthesis is elevated after morphine treatment of astrocyte-enriched cultures or brain slices [5]. This change in astrocyte function suggested that (unspecified) proteins released from astrocytes alter neuronal responses to morphine, creating tolerance [5]. Thirteen years lapsed
Glia as counter-regulators of morphine
The existence of both pain-inhibitory and pain-facilitatory mechanisms implies that pain experienced by an individual is determined by summation of the activity in these systems. As already summarized, there is strong evidence that peripheral nerve injury activates spinal cord glia, and that this glial activation is intimately involved in the induction and maintenance of neuropathic pain. Notably, there are striking similarities between neuropathic pain and morphine tolerance [31]. For example,
Potential mechanisms and mediators
Data suggest that morphine stimulates production of proinflammatory cytokines, which counterbalance morphine analgesia by creating compensatory pain facilitation (Figure 5). Indeed, intrathecal IL-1 [11] and IL-6 [10] enhance pain responsivity, and IL-1 [11] and TNF [52] induce spontaneous and enhanced evoked activity in pain-responsive neurons. The effects of proinflammatory cytokines might be direct, via cytokine receptors expressed by spinal neurons [53], and/or might be indirect, via
Implications and conclusions
The implications of these studies are clear. Spinal cord glia are sensitive to and activated by many perturbations. Activation can occur in response to peripheral or central inflammation or infection, in response to peripheral injury as occurs in neuropathy, or in response to drugs such as morphine (Figure 5). Whether glia are activated in their role as immune-like cells in response to neuron-to-glia signals or in response to morphine, the end result is strikingly similar. That is, activated
Acknowledgements
This work was supported by NIH grants DA015656, DA015642, NS40696 and NS38020, and an International Association for the Study of Pain International Collaborative Research grant.
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