Glia as the “bad guys”: Implications for improving clinical pain control and the clinical utility of opioids

Within the past decade, there has been increasing recognition that glia are far more than simply “housekeepers” for neurons. This review explores two recently recognized roles of glia (microglia and astrocytes) in: (a) creating and maintaining enhanced pain states such as neuropathic pain, and (b) compromising the eYcacy of morphine and other opioids for pain control. While glia have little-to-no role in pain under basal conditions, pain is ampliWed when glia become activated, inducing the release of proinXammatory products, especially proinXammatory cytokines. How glia are triggered to become activated is a key issue, and appears to involve a number of neuron-to-glia signals including neuronal chemokines, neurotransmitters, and substances released by damaged, dying and dead neurons. In addition, glia become increasingly activated in response to repeated administration of opioids. Products of activated glia increase neuronal excitability via numerous mechanisms, including direct receptor-mediated actions, upregulation of excitatory amino acid receptor function, downregulation of GABA receptor function, and so on. These downstream eVects of glial activation amplify pain, suppress acute opioid analgesia, contribute to the apparent loss of opioid analgesia upon repeated opioid administration (tolerance), and contribute to the development of opioid dependence. The potential implications of such glial regulation of pain and opioid actions are vast, suggestive that targeting glia and their proinXammatory products may provide a novel and eVective therapy for controlling clinical pain syndromes and increasing the clinical utility of analgesic drugs.  2006 Elsevier Inc. All rights reserved.