title: Glial dysfunction and persistent neuropathic postsurgical pain.
abstract: Acute pain in response to injury is an important mechanism that serves to protect living beings from harm. However, persistent pain remaining long after the injury has healed serves no useful purpose and is a disabling condition. Persistent postsurgical pain, which is pain that lasts more than 3 months after surgery, affects 10-50% of patients undergoing elective surgery. Many of these patients are affected by neuropathic pain which is characterised as a pain caused by lesion or disease in the somatosensory nervous system. When established, this type of pain is difficult to treat and new approaches for prevention and treatment are needed. A possible contributing mechanism for the transition from acute physiological pain to persistent pain involves low-grade inflammation in the central nervous system (CNS), glial dysfunction and subsequently an imbalance in the neuron-glial interaction that causes enhanced and prolonged pain transmission.
  
  
  
  This topical review aims to highlight the contribution that inflammatory activated glial cell dysfunction may have for the development of persistent pain.
  
  
  
  Relevant literature was searched for in PubMed.
  
  
  
  Immediately after an injury to a nerve ending in the periphery such as in surgery, the inflammatory cascade is activated and immunocompetent cells migrate to the site of injury. Macrophages infiltrate the injured nerve and cause an inflammatory reaction in the nerve cell. This reaction leads to microglia activation in the central nervous system and the release of pro-inflammatory cytokines that activate and alter astrocyte function. Once the astrocytes and microglia have become activated, they participate in the development, spread, and potentiation of low-grade neuroinflammation. The inflammatory activated glial cells exhibit cellular changes, and their communication to each other and to neurons is altered. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocyte dysfunction can be experimentally restored using the combined actions of a μ-opioid receptor agonist, a μ-opioid receptor antagonist, and an anti-epileptic agent. To find these agents we searched the literature for substances with possible anti-inflammatory properties that are usually used for other purposes in medicine. Inflammatory induced glial cell dysfunction is restorable in vitro by a combination of endomorphine-1, ultralow doses of naloxone and levetiracetam. Restoring inflammatory-activated glial cells, thereby restoring astrocyte-neuron interaction has the potential to affect pain transmission in neurons.
  
  
  
  Surgery causes inflammation at the site of injury. Peripheral nerve injury can cause low-grade inflammation in the CNS known as neuroinflammation. Low-grade neuroinflammation can cause an imbalance in the glial-neuron interaction and communication. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocytic dysfunction can be restored in vitro by a combination of endomorphin-1, ultralow doses of naloxone and levetiracetam. This restoration is essential for the interaction between astrocytes and neurons and hence also for modulation of synaptic pain transmission.
  
  
  
  Larger studies in clinical settings are needed before these findings can be applied in a clinical context. Potentially, by targeting inflammatory activated glial cells and not only neurons, a new arena for development of pharmacological agents for persistent pain is opened.
authors.affiliation: Institute of Clinical Sciences at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Department of Anesthesiology and Intensive Care, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Block
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D016207:Cytokines; D006801:Humans; D007249:Inflammation; D017628:Microglia; D009437:Neuralgia; D009457:Neuroglia / Q000473:pathology*; D010149:Postoperative Pain / Q000503:physiopathology*; D059348:Peripheral Nerve Injuries / Q000276:immunology*; D010525:Peripheral Nerves; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines
keywords: Glia; Neuroinflammation; Neuropathic pain; Pain; Persistent postsurgical pain