Articles: hyperalgesia.
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Vascular endothelial growth factor (VEGF)-A mRNA was previously identified as one of the significantly upregulated transcripts in spinal cord injured tissue from adult rats that developed allodynia. To characterize the role of VEGF-A in the development of pain in spinal cord injury (SCI), we analyzed mechanical allodynia in SCI rats that were treated with either vehicle, VEGF-A isoform 165 (VEGF(165)), or neutralizing VEGF(165)-specific antibody. We have observed that exogenous administration of VEGF(165) increased both the number of SCI rats that develop persistent mechanical allodynia, and the level of hypersensitivity to mechanical stimuli. ⋯ It is possible that another endogenous VEGF isoform activates the same signaling pathway as the exogenously-administered 165 isoform and contributes to SCI pain. Our transcriptional analysis revealed that endogenous VEGF(188) is likely to be the isoform involved in the development of allodynia after SCI. To the best of our knowledge, this is the first study to suggest a possible link between VEGF, nonspecific sprouting of myelinated axons, and mechanical allodynia following SCI.
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Journal of neurochemistry · Oct 2010
Light touch induces ERK activation in superficial dorsal horn neurons after inflammation: involvement of spinal astrocytes and JNK signaling in touch-evoked central sensitization and mechanical allodynia.
Activation of extracellular signal-regulated kinase (ERK) in spinal cord neurons could serve as a marker for sensitization of dorsal horn neurons in persistent pain. ERK is normally activated by high-threshold noxious stimuli. We investigated how low-threshold mechanical stimuli could activate ERK after complete Freund's adjuvant (CFA)-induced inflammation. ⋯ Intrathecal administration of the astroglial toxin L-α-aminoadipate on post-CFA day 2 reversed CFA-induced bilateral mechanical allodynia but not heat hyperalgesia. Furthermore, L-α-aminoadipate, the glial inhibitor fluorocitrate, and a peptide inhibitor of c-Jun N-terminal Kinase all reduced light touch-evoked ERK activation ipsilateral to touch. Collectively, these data suggest that (i) ERK can be activated in superficial dorsal horn neurons by low-threshold mechanical stimulation under pathological condition and (ii) ERK activation by light touch is associated with mechanical allodynia and requires an astrocyte network.
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Clinical observations suggest that depressed patients were less sensitive to experimental pain than healthy subjects. However, few animal studies are reported concerning the association of depression and pain. The purpose of this study was to investigate the effects of unpredictable chronic mild stress (UCMS) induced depression on the perceived intensity of painful stimulation in rats. ⋯ The results showed that rats exposed to UCMS exhibited significantly higher thermal and mechanical pain thresholds in comparison to the non-depressed controls. In particular, the PWT of the SNL group was restored to nearly normal level after three weeks of UCMS, and even comparable to that of the control group. These results strongly suggest that the depressed subjects have decreased sensitivity to externally applied noxious stimulation, which is consistent with our previous findings.
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Hyperexcitability of peripheral nociceptive pathways is often associated with inflammation and is an important mechanism underlying inflammatory pain. Here we describe a completely novel mechanism via which nociceptor G-protein-coupled receptor kinase 2 (GRK2) contributes to regulation of inflammatory hyperalgesia. We show that nociceptor GRK2 is downregulated during inflammation. ⋯ In conclusion, we discovered GRK2 as a novel Epac1-interacting protein. A reduction in the cellular level of GRK2 enhances activation of the Epac-Rap1 pathway. In vivo, low nociceptor GRK2 leads to prolonged inflammatory hyperalgesia via biased cAMP signaling from PKA to Epac-Rap1, ERK/PKCε pathways.