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, 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.

Figure 1

Microglial reaction in the spinal dorsal horn of rats after nerve injury and paw incision. (A) OX-42 immunoflurorescence (dark field) in the dorsal horn one day after spinal nerve ligation. The lesion side shows marked microglial activation in comparison with the contralateral side. (B) Immunohistochemical staining (bright field) of Iba-1 in the dorsal horn one day after plantar incision. The reactive microglia in the injured side display a dense and amoeboid appearance in contrast to the ramified morphology of microglia in the contralateral side. Scar bar: 100 µm.

Figure 2

Schematic illustration of microglia-evoked pain. Nerve injury, surgical procedures, and chronic opoid exposure result in activation of microglial cells in the spinal cord. This activation could be initiated by the release of ATP, matrix metalloprotease-9 (MMP-9), and the chemokine fractalkine (FKN/CX3CL1), leading to the phosphorylation of p38 MAPK in microglia. Activation of p38 induces the synthesis and release of several pain mediators including the proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and neurotrophin (BDNF) from microglia. These glia-produced pain mediators can initiate and maintain postoperative pain, neuropathic pain, and antinociceptive tolerance of opioids, via inducing hyperexcitability of nociceptive neurons in the spinal cord dorsal horn.