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. 2011 Jul 27:7:52.
doi: 10.1186/1744-8069-7-52.

Streptozotocin-induced early thermal hyperalgesia is independent of glycemic state of rats: role of transient receptor potential vanilloid 1(TRPV1) and inflammatory mediators

Mahendra Bishnoi  1 , Christine A Bosgraaf, Mruvil Abooj, Linlin Zhong, Louis S Premkumar
Affiliations

Streptozotocin-induced early thermal hyperalgesia is independent of glycemic state of rats: role of transient receptor potential vanilloid 1(TRPV1) and inflammatory mediators

Mahendra Bishnoi et al. Mol Pain. .

Abstract

Background: Streptozotocin (STZ) is used as a common tool to induce diabetes and to study diabetes-induced complications including diabetic peripheral neuropathy (DPN). Previously, we have reported that STZ induces a direct effect on neurons through expression and function of the Transient receptor potential vanilloid 1 (TRPV1) channel in sensory neurons resulting in thermal hyperalgesia, even in non-diabetic STZ-treated mice. In the present study, we investigated the role of expression and function of TRPV1 in the central sensory nerve terminals in the spinal cord in STZ-induced hyperalgesia in rats.

Results: We found that a proportion of STZ-treated rats were normoglycemic but still exhibited thermal hyperalgesia and mechanical allodynia. Immunohistochemical data show that STZ treatment, irrespective of glycemic state of the animal, caused microglial activation and increased expression of TRPV1 in spinal dorsal horn. Further, there was a significant increase in the levels of pro-inflammatory mediators (IL-1β, IL-6 and TNF-α) in spinal cord tissue, irrespective of the glycemic state. Capsaicin-stimulated release of calcitonin gene related peptide (CGRP) was significantly higher in the spinal cord of STZ-treated animals. Intrathecal administration of resiniferatoxin (RTX), a potent TRPV1 agonist, significantly attenuated STZ-induced thermal hyperalgesia, but not mechanical allodynia. RTX treatment also prevented the increase in TRPV1-mediated neuropeptide release in the spinal cord tissue.

Conclusions: From these results, it is concluded that TRPV1 is an integral component of initiating and maintaining inflammatory thermal hyperalgesia, which can be alleviated by intrathecal administration of RTX. Further, the results suggest that enhanced expression and inflammation-induced sensitization of TRPV1 at the spinal cord may play a role in central sensitization in STZ-induced neuropathy.

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Figures

Figure 1
Figure 1
Changes in blood glucose levels, body weight, glucose tolerance, plasma insulin level, thermal pain sensitivity, mechanical allodynia in STZ-treated hyperglycemic (STZ-HG) rats. A. Within a week after intraperitoneal injection of STZ, blood glucose levels (BGL) significantly increased (p < 0.001) and remained constant throughout the course of the experiment as compared to vehicle-treated rats. B. The body weight of STZ-HG rats (filled circles, n = 18) decreased, whereas body weight of vehicle-treated rats (filled squares, n = 10) increased steadily over the course of 5 weeks. C. Glucose tolerance test (GTT) in STZ-HG and vehicle-treated rats 5 weeks after STZ administration. D. Plasma insulin levels were significantly lower (p < 0.05) in STZ-HG rats as compared to vehicle-treated rats. E. STZ-HG rats exhibited a significant decrease in PWL (p < 0.05) as compared to vehicle-treated rats. F. STZ-HG rats exhibited a significant (p < 0.05) decrease in PWT after 3 weeks of STZ administration as compared to vehicle-treated rats. Asterisks (*, **) represent p < 0.05 and p < 0.001, respectively.
Figure 2
Figure 2
Changes in blood glucose levels, body weight, glucose tolerance, plasma insulin levels, thermal pain sensitivity, mechanical allodynia in STZ-treated normoglycemic (STZ-NG) rats. A. Blood glucose levels (BGL) remained constant throughout the course of the experiment in STZ-NG and vehicle-treated rats. B. The body weight of STZ-NG rats (filled circles, n = 12) and vehicle-treated rats (filled squares, n = 10) increased steadily over the course of 5 weeks C. Glucose tolerance test (GTT) in STZ-NG and vehicle-treated rats after 5 weeks of STZ administration. D. Plasma insulin levels were unchanged in STZ-NG rats as compared to vehicle-treated rats. E. STZ-NG rats exhibited a significant decrease (p < 0.05) in PWL as compared to vehicle-treated rats. F. STZ-NG rats exhibited a significant (p < 0.05) decrease in PWT after 3 weeks of STZ administration as compared to vehicle-treated rats. Asterisk (*) represent p < 0.05.
Figure 3
Figure 3
Altered microglial activation in spinal cord dorsal horn of STZ-treated rats. A. Representative images of OX-42 staining (marker for microglial activation) from a vehicle-treated, STZ-HG and STZ-NG rats. B. Average gray values/10,000 μm2 area of OX-42 staining in spinal dorsal horn was significantly increased (p < 0.05) in both STZ-HG and STZ-NG rats as compared to vehicle-treated rats. Asterisk (*) represents p < 0.05. Scale bar is 50 μm.
Figure 4
Figure 4
Altered TRPV1 staining in spinal cord dorsal horn of STZ-treated rats. A. Representative images of TRPV1 staining from a vehicle-treated, STZ-HG and STZ-NG rats. An enlarged segment has also been shown. B. Average gray values/10,000 μm2 area of TRPV1 staining in dorsal horn was significantly increased (p < 0.05) in both STZ-HG and STZ-NG rats as compared to vehicle-treated rats. Asterisk (*) represents p < 0.05. Scale bar is 200 μm and 50 μm for upper and lower panels, respectively.
Figure 5
Figure 5
Effect of intraperitoneal administration of STZ on spinal pro-inflammatory cytokine levels. Interleukin-1β(IL-1β)(A), Interleukin-6(IL-6)(B), Tumor necrosis factor-α (TNF-α)(C) in lumbar spinal cord tissue homogenates. Asterisk (*) represent p < 0.05 as compared to vehicle-treated rats.
Figure 6
Figure 6
Change in basal and capsaicin-evoked CGRP release in STZ-treated rats A. Basal CGRP release in spinal dorsal horn was unaffected after STZ treatment B. Both STZ-HG and STZ-NG rats show a significant increase in the capsaicin evoked-CGRP release C. Intrathecal RTX treatment prevent the increase in capsaicin evoked-CGRP release in STZ-treated rats. Asterisks (*, +) represent p < 0.05 as compared to vehicle and evoked vehicle-treated rats respectively.
Figure 7
Figure 7
Effect of intrathecal administration of RTX on STZ-induced thermal hyperalgesia and mechanical allodynia. A.B. RTX attenuated thermal hyperalgesia in both STZ-HG and STZ-NG rats. C.D. RTX administration 2 weeks after STZ injection did not have any effect on mechanical allodynia in both STZ-HG and STZ-NG rats. Asterisks (*, #) represent p < 0.05 as compared to vehicle treated and STZ-HG/STZ-NG rats respectively.
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