Microglia: A Promising Target for Treating Neuropathic and Postoperative Pain, and Morphine Tolerance

Abstract

Management of chronic pain such as nerve injury-induced neuropathic pain associated with diabetic neuropathy, viral infection, and cancer is a real clinical challenge. Major surgeries such as breast and thoracic surgery, leg amputation, and coronary artery bypass surgery also lead to chronic pain in 10–50% of individuals after acute postoperative pain, in part due to surgery-induced nerve injury. Current treatments mainly focus on blocking neurotransmission in the pain pathway and have only resulted in limited success. Ironically, chronic opioid exposure may lead to paradoxical pain. Development of effective therapeutic strategies requires a better understanding of cellular mechanisms underlying the pathogenesis of neuropathic pain. An important progress in pain research points to important role of microglial cells in the development of chronic pain. Spinal cord microglia are strongly activated after nerve injury, surgical incision, and chronic opioid exposure. Increasing evidence suggests that under all these conditions the activated microglia not only exhibit increased expression of microglial markers CD11b and Iba1 but also display elevated phosphorylation of p38 MAP kinase. Inhibition of spinal cord p38 has been shown to attenuate neuropathic pain and postoperative pain, as well as morphine-induced antinociceptive tolerance. Activation of p38 in spinal microglia results in increased synthesis and release of the neurotrophin BDNF and the proinflammatory cytokines IL-1β, IL-6, and TNF-α. These microglia-released mediators can powerfully modulate spinal cord synaptic transmission, leading to increased excitability of dorsal horn neurons, i.e. central sensitization, in part via suppressing inhibitory synaptic transmission. We review the studies that support the pronociceptive role of microglia in conditions of neuropathic pain, post-surgical pain, and opioid tolerance. Some of these studies have been accomplished by four Taiwanese anesthesiologists who are also co-authors of this review during their training at Harvard Medical School. We conclude that targeting microglial signalling may lead to more effective treatments for devastating chronic pain after diabetic neuropathy, viral infection, cancer, and major surgeries in part via improving the analgesic efficacy of opioids.

Potential strategies for preventing chronic postoperative pain: a practical approach: Continuing Professional Development

“…17,[22][23][24] More recently, numerous authors have reported that glial cells (microglia and astrocytes), activated by the inflammatory response to the surgical insult, play an important role in the induction and maintenance of the central sensitization that leads to PPSP. 19,20,23 Briefly, inflammation activates macrophages which activate microglial cells in DRGs and astrocytes in the central nervous system (CNS). Activated microglial cells induce an increase in pro-inflammatory cytokines such as interleukins (IL)-1b, IL-6, tumour necrosis factora, and brain-derived neurotrophic factor.…”

“…Lorsqu'elle s'installe, cette plasticité neuronale entraîne des changements dans la fonction et la structure des neurones pouvant expliquer les DCPC. 17,[22][23][24] Plus récemment, de nombreux auteurs ont rapporté que les cellules gliales (microglie et astrocytes), activées par les réponses inflammatoires au traumatisme chirurgical, jouaient un rôle important dans l'induction et le maintien d'une sensibilisation centrale qui aboutit aux DCPC. 19,20,23 Brièvement, l'inflammation active les macrophages.…”

Efficacy and safety of lithium carbonate treatment of chronic spinal cord injuries: a double-blind, randomized, placebo-controlled clinical trial

“…37 Parkitna et al 38 reported that a single intrathecal injection of GSK3b inhibitor can restore the analgesic effect of morphine in morphinetolerant rats.…”

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

“…Chronic administration of morphine also results in pain-related activation of neurons and glia, and induces the release of pro-infl ammatory cytokines and chemokines [15][16][17] . The prevailing evidence shows that acute and chronic morphine treatment increases the expression of TNF-α, IL-1β, and IL-6 in activated glia in the DRG and spinal cord, which ultimately results in the decreased analgesic efficacy of morphine.…”