Abstract
Diabetic neuropathic pain (DNP) is one of the most common clinical manifestations of diabetes mellitus (DM), which is characterized by prominent mechanical allodynia (DMA). However, the molecular mechanism underlying it has not fully been elucidated. In this study, we examined the spatio-temporal expression of a major nociceptive channel protein transient receptor potential vanilloid 1 (TRPV1) and analyzed its functional involvement by intrathecal (i.t.) application of TRPV1 antagonists in streptozocin (STZ)-induced DMA rat models. Western blot and immunofluorescent staining results showed that TRPV1 protein level was significantly increased in the soma of the dorsal root ganglion (DRG) neurons on 14 days after STZ treatment (DMA 14 d), whereas those in spinal cord and skin (mainly from the central and peripheral processes of DRG neurons) had already been enhanced on DMA 7 d to peak on DMA 14 d. qRT-PCR experiments confirmed that TRPV1 mRNA level was significantly up-regulated in the DRG on DMA 7 d, indicating a preceding translation of TRPV1 protein in the soma but preferential distribution of this protein to the processes under the DMA conditions. Cell counting assay based on double immunostaining suggested that increased TRPV1-immunoreactive neurons were likely to be small-sized and CGRP-ergic. Finally, single or multiple intrathecal applications of non-specific or specific TRPV1 antagonists, ruthenium red and capsazepine, at varying doses, effectively alleviated DMA, although the effect of the former was more prominent and long-lasting. These results collectively indicate that TRPV1 expression dynamically changes during the development of DMA and this protein may play important roles in mechanical nociception in DRG neurons, presumably through facilitating the release of CGRP.
Highlights
Diabetic neuropathic pain (DNP) is one of the most common complications that affects approximately 20% of patients with diabetes mellitus (DM) in the world [1,2]
Another important index to assess DM, body weight increase, was significantly impaired after the injection of STZ ensuring the successful establishment of DM in the present rat model (Fig. 1B)
No obvious differences were observed in the percentage of transient receptor potential vanilloid 1 (TRPV1)/isolectin B4 (IB4) dual-positive to IB4-IR neurons between the two groups under the same conditions (Fig. 6M-R; Table 2, the lower row). These findings strongly suggest that increased TRPV1-IR neurons in dorsal root ganglion (DRG) pertain mainly to a class of CGRP-containing peptidergic neurons, but not to NF200-labeled or IB4-positive neurons, under DMA conditions
Summary
Diabetic neuropathic pain (DNP) is one of the most common complications that affects approximately 20% of patients with diabetes mellitus (DM) in the world [1,2]. Evidence from rodent models suggested that, under inflammatory and neuropathic conditions, the expression level and/or the functionality of TRPV1 were up-regulated in dorsal root ganglion (DRG), spinal dorsal horn and the endogenous antinociceptive center, periaqueductal grey [8,9,10]. These findings imply the essential involvement of TRPV1 channel in pain signal transduction and integration. Consistent with this view, thermal hyperalgesia and mechanical allodynia derived from inflammation or nerve injury were reported to be alleviated by down-regulating TRPV1 expression or pharmacologically inhibiting the channel activity [11,12,13]
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