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 efficacy of
morphine and other
opioids for
pain control. While glia have little-to-no role in
pain under basal conditions,
pain is amplified when glia become activated, inducing the release of proinflammatory products, especially proinflammatory
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 effects 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 proinflammatory products may provide a novel and effective
therapy for controlling clinical
pain syndromes and increasing the clinical utility of
analgesic drugs.