Abstract
Background
Long-term or chronic pain represents a major health problem and is associated with significant socio-economic costs. During injury, pain can be dissociated from its normal physiological role. It can persist for a longer period of time, even after the primary noxious stimulus has more or less subsided. Analgesic drugs, with predominant neuronal sites of actions, seem to be relatively ineffective. Chronic pain is probably partly a consequence of ongoing neuroinflammation. The mechanisms behind these phenomena, and how the neuronal and non-neuronal activities evoked by painful stimuli and inflammation are processed in the brain and throughout the CNS, are not well understood.
Methods
Primary cultures, calcium imaging, immunocyto-chemistry, Western blotting, cytokine release.
Results
Following pain stimuli increased activity of inflammatory receptors and shifts in intra- and extracellular ion concentrations occur within the CNS. One signalling pathway in astrocytes propagates Ca2+ waves, which initially decrease and then increase in form of oscillations in the astrocyte networks. This causes dysfunction in the astrocytic Ca2+ signalling resulting in down-regulation of Na+ transporters, and increased release of pro-inflammatory cytokines. The neurons will then increase their excitability and, hypothetically, also increase the sensitivity for development or potentiation of neuropathic pain states. Low-dose of potential anti-inflammatory and analgesic drugs restore the disturbed astrocytic Ca2+ signalling, and modulate the activity of inflammatory receptors and Na+/K+-ATPase. We recently report, in patients with long-term pain, changes in neurotrophic factors and pro-inflammatory cytokines in blood and CSF.
Conclusions
Dysfunction in downregulation of Na+ transporters, changed Ca2+ signalling in the astrocyte networks and release of cytokines from glial cells can lead to pathogenic chronic neuroinflammation. Modulation of the Na+/K+-ATPase activity and restoration with anti-inflammatory substances will lead to a balance between inflammatory and anti-inflammatory mediators in inflammatory reactive cells. The pharmacological treatment of today is directed towards neuronal over-excitability, unfortunately with less success. A novel pharmacological treatment strategy would thus be directed towards the activated astrocytes and microglial cells, being the source of the neuroinflammation. This will be an important knowledge for treatment in clinical therapy.
The use of analgesic drugs by South African veterinarians : continuing education