TY - JOUR
T1 - Microglia
T2 - A promising target for treating neuropathic and postoperative pain, and morphine tolerance
AU - Wen, Yeong-Ray
AU - Tan, Ping Heng
AU - Cheng, Jen Kun
AU - Liu, Yen Chin
AU - Ji, Ru Rong
N1 - Funding Information:
This study was supported in part by National Institutes of Health grants NS54932 and DE17794 to R.R.J; NSC grants 97-2314-B-341-002-MY3 and SKH-8302-98-DR-32 to Y.R.W; NSC grants 97-2314-B-214-006-MY3, EDPJ 98023, 99038 and EDAHP 99030 to P.H.T; NSC grant 98-2314-B-195-002-MY3 to J.K.C; and NSC grant 97-2918-I-006-012 to Y.C.L.
PY - 2011/8
Y1 - 2011/8
N2 - 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 CD11b and Iba1, 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.
AB - 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 CD11b and Iba1, 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.
KW - Central sensitization
KW - Neuronal-glial interactions
KW - p38 mitogen-activated protein kinase
KW - Proinflammatory cytokines
KW - Spinal cord
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U2 - 10.1016/S0929-6646(11)60074-0
DO - 10.1016/S0929-6646(11)60074-0
M3 - Review article
C2 - 21783017
AN - SCOPUS:79960807502
SN - 0929-6646
VL - 110
SP - 487
EP - 494
JO - Journal of the Formosan Medical Association
JF - Journal of the Formosan Medical Association
IS - 8
ER -