Microglia: A Promising Target for Treating Neuropathic Pain

Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness.

Abstract

Microglia play a crucial role in the maintenance of neuronal homeostasis in the central nervous system, and microglia production of immune factors is believed to play an important role in nociceptive transmission. There is increasing evidence that uncontrolled activation of microglial cells under neuropathic pain conditions induces the release of proinflammatory cytokines (interleukin – IL-1beta, IL-6, tumor necrosis factor – TNF-alpha), complement components (C1q, C3, C4, C5, C5a) and other substances that facilitate pain transmission. Additionally, microglia activation can lead to altered activity of opioid systems and neuropathic pain is characterized by resistance to morphine. Pharmacological attenuation of glial activation represents a novel approach for controlling neuropathic pain. It has been found that propentofylline, pentoxifylline, fluorocitrate and minocycline decrease microglial activation and inhibit proinflammatory cytokines, thereby suppressing the development of neuropathic pain. The results of many studies support the idea that modulation of glial and neuroimmune activation may be a potential therapeutic mechanism for enhancement of morphine analgesia. Researchers and pharmacological companies have embarked on a new approach to the control of microglial activity, which is to search for substances that activate anti-inflammatory cytokines like IL-10. IL-10 is very interesting since it reduces allodynia and hyperalgesia by suppressing the production and activity of TNF-alpha, IL-1beta and IL-6. Some glial inhibitors, which are safe and clinically well tolerated, are potential useful agents for treatment of neuropathic pain and for the prevention of tolerance to morphine analgesia. Targeting glial activation is a clinically promising method for treatment of neuropathic pain.

Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance.

Source

Department of Anesthesiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.

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, partly 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 might lead to paradoxical pain. Development of effective therapeutic strategies requires a better understanding of cellular mechanisms underlying the pathogenesis of neuropathic pain. Progress in pain research points to an 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 CD 11 b and Iba 1, but also display elevated phosphorylation of p38 mitogen-activated protein kinase. Inhibition of spinal cord p38 has been shown to attenuate neuropathic 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 brain-derived neurotrophic factor and the proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α. These microglia-released mediators can powerfully modulate spinal cord synaptic transmission, leading to increased excitability of dorsal horn neurons, that is, central sensitization, partly via suppressing inhibitory synaptic transmission. Here, we review studies that support the pronociceptive role of microglia in conditions of neuropathic and postoperative pain and opioid tolerance. We conclude that targeting microglial signaling might lead to more effective treatments for devastating chronic pain after diabetic neuropathy, viral infection, cancer, and major surgeries, partly via improving the analgesic efficacy of opioids.

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