Altered neuronal-glial signaling in glutamatergic transmission as a unifying mechanism in chronic pain and mental fatigue.
Recent experimental results have demonstrated a glial activation during long-term pain that produces and releases cytokines, free oxygen radicals, nitric oxide, and other neuroactive substances in the spinal cord dorsal horns. Such activation might generate a vicious circle by increasing the neuronal excitability level due to a decreased astroglial glutamate uptake and thereby reinforce pain signals that travel up to the thalamus and further up into the parietal cortex for identification and interpretation. In this paper, we adapt new knowledge on neuronal-glial signaling in the CNS to develop tentative explanations at the cellular level for the maintenance of pain signals in the brain, for formation of "pain memory," and even for the increased pain sensitivity that persons with chronic pain often experience in body regions other than those originally affected. We also suggest a hypothetical mechanism at the cellular level underlying the mental fatigue from which persons with chronic pain may suffer. This hypothesis relies on the impaired astroglial glutamate uptake capacity due to the production of neuroactive substances, altered conditions in the chronic pain state, and the anxiety and stress reactions that may occur secondary to the pain. Neuronal activity over time in the dysfunctional state of the astroglial network leads to an increase in extracellular glutamate levels in the vicinity of glutamate synapses. In turn, this increase leads over time to less precision in glutamate transmission. The increased extracellular glutamate levels lead to increased excitability and increased energy requirements. When cellular energy decreases the glutamate transmission decreases, and according to our hypothesis, this is one cause of mental fatigue. New strategies for treatment of chronic pain and the associated mental fatigue are formulated and should be explored.
Hansson
Elisabeth
E
Institute of Clinical Neuroscience, Göteborg University, Medicinaregatan 5, P.O. Box 420, SE 405 30 Göteborg, Sweden. elisabeth.hansson@anatcell.gu.se
Rönnbäck
Lars
L
D000818:Animals; D002908:Chronic Disease; D018698:Glutamic Acid / Q000502:physiology; D006801:Humans; D005222:Mental Fatigue; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D010146:Pain / Q000503:physiopathology; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology
D018698:Glutamic Acid