Norman Cousins Lecture. 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 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.
Watkins
Linda R
LR
Department of Psychology and the Center for Neuroscience, Muenzinger D-244, Campus Box 345, University of Colorado at Boulder, Boulder, CO 80309-0345, USA. linda.watkins@colorado.edu
Hutchinson
Mark R
MR
Ledeboer
Annemarie
A
Wieseler-Frank
Julie
J
Milligan
Erin D
ED
Maier
Steven F
SF
D000698:Analgesia / Q000379:methods*; D000701:Analgesics, Opioid / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D018925:Chemokines / Q000378:metabolism; D006801:Humans; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology
D000701:Analgesics, Opioid; D018925:Chemokines; D018377:Neurotransmitter Agents