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Abstract
Hyperalgesia results from a decreased pain threshold, often subsequent to peripheral tissue damage. Recent reports revealed several promising mechanisms of hyperalgesia, but many issues remain unclear. The glial activation accompanying inflammation of neurotransmission in the spinal cord might be related to the initiation and maintenance of hyperalgesia. The present study investigated the pharmacological pain-modifying effects of mitogen-associated protein kinase (MAPK)-related inhibitors identified with glia cells over time during inflammatory pain. A model of inflammatory pain was produced by injecting mustard oil (MO) into the hind paws of rats. Following MO injection, the changes in paws flinching as the early onset of pain and paw withdrawal latency (PWL) in response to thermal stimulation were measured as delayed-onset hyperalgesia. Before and after the MO injection, one of the inhibitors, a p38-MAPK (SB), nuclear factor (NF)-κB (PDTC), BDNF-trk-B (K252a), or JNK-1 (SP), was administered and flinching and PWL were measured. In the SB, PDTC, and k252a groups, early flinching following MO injection was moderately suppressed. Hyperalgesia was significantly suppressed in the left–right difference of PWL in animals receiving SB, k252a, or PDTC pre-treatment. In animals receiving post-treatment, the suppressive effects were most potent in the SP group. The present results revealed that microglial activation resulting from the release of the phosphatase p38-MAPK, the transcription factor NF-κB, and BDNF contributes to the early stage of inflammatory pain. Astrocyte activation accompanying JNK activation contributes to subsequent hyperalgesia. Activation of different signals identified with glia cells is thought to contribute to the progression of hyperalgesia, which represents an applicable finding for the treatment of hyperalgesia.
Highlights
Recent studies have suggested that persistent pain is a reflection of neural plasticity that may reflect excessive neurotransmission related to abnormal intracellularCell Mol Neurobiol (2013) 33:167–174 signaling and dysfunction of inhibitory neurons in the spinal and supraspinal cord (Woolf and Salter 2000; Zhuo 2007)
The present results revealed that microglial activation resulting from the release of the phosphatase p38-mitogen-associated protein kinase (MAPK), the transcription factor nuclear factor-jB (NF-jB), and brain-derived neurotrophic factor (BDNF) contributes to the early stage of inflammatory pain
It is well known that once activated by phosphorylation, MAPK facilitates exaggerated intra-cellular signaling followed by nuclear process extracellular signal-regulated kinase (ERK), cAMP response elementbinding protein (CREB), and nuclear factor-jB (NF-jB)
Summary
Recent studies have suggested that persistent pain is a reflection of neural plasticity that may reflect excessive neurotransmission related to abnormal intracellularCell Mol Neurobiol (2013) 33:167–174 signaling and dysfunction of inhibitory neurons in the spinal and supraspinal cord (Woolf and Salter 2000; Zhuo 2007). Intracellular phosphates and members of the mitogenassociated protein kinase (MAPK) family that can modulate glia activity (Svensson et al 2003; Hua et al 2005; Ji and Suter 2007) and brain-derived neurotrophic factor (BDNF) derived from neurons or glia (Ji and Suter 2007; Zhou et al 2008) are thought to contribute to the process of pain facilitation following tissue damage. Inhibition of intracellular signaling may be effective for reduction of pain facilitation (Svensson et al 2003; Zhuo 2007). It is well known that once activated by phosphorylation, MAPK facilitates exaggerated intra-cellular signaling followed by nuclear process ERK, cAMP response elementbinding protein (CREB), and nuclear factor-jB (NF-jB). Characterizing changes over time in the phosphatase-related activity associated with these abnormal pain states would help elucidation of the mechanisms underlying neuroglial interactions in the pain pathways
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