Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity

A common complication associated with diabetes is painful or painless diabetic peripheral neuropathy (DPN). The mechanisms and determinants responsible for these peripheral neuropathies are poorly understood. Using both streptozotocin (STZ)-induced and transgene-mediated murine models of type 1 diabetes (T1D), we demonstrate that Transient Receptor Potential Vanilloid 1 (TRPV1) expression varies with the neuropathic phenotype. We have found that both STZ- and transgene-mediated T1D are associated with two distinct phases of thermal pain sensitivity that parallel changes in TRPV1 as determined by paw withdrawal latency (PWL). An early phase of hyperalgesia and a late phase of hypoalgesia are evident. TRPV1-mediated whole cell currents are larger and smaller in dorsal root ganglion (DRG) neurons collected from hyperalgesic and hypoalgesic mice. Resiniferatoxin (RTX) binding, a measure of TRPV1 expression is increased and decreased in DRG and paw skin of hyperalgesic and hypoalgesic mice, respectively. Immunohistochemical labeling of spinal cord lamina I and II, dorsal root ganglion (DRG), and paw skin from hyperalgesic and hypoalgesic mice reveal increased and decreased TRPV1 expression, respectively. A role for TRPV1 in thermal DPN is further suggested by the failure of STZ treatment to influence thermal nociception in TRPV1 deficient mice. These findings demonstrate that altered TRPV1 expression and function contribute to diabetes-induced changes in thermal perception

HRTX binding in DRG neurons and paw skin obtained from STZ-induced diabetic mice

. Diabetic hyperalgesic and hypoalgesic mice DRG exhibited higher (n = 4 experiments, p < 0.05) and lower (n = 3 experiments, p < 0.05) TRPV1 levels, respectively as compared to control non-diabetic mice. . Paw tissue obtained from STZ-induced diabetic hyperalgesic and hypoalgesic mice expressed higher (n = 5 experiments, p < 0.05) and lower (n = 5 experiments, p < 0.05) TRPV1 levels, respectively as compared with control non-diabetic mice. Number in the parenthesis represents the number of experiments performed and the asterisk (*) represents < 0.05.<p><b>Copyright information:</b></p><p>Taken from "Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity"</p><p>http://www.molecularpain.com/content/4/1/9</p><p>Molecular Pain 2008;4():9-9.</p><p>Published online 1 Mar 2008</p><p>PMCID:PMC2275252.</p><p></p

Altered TRPV1 staining is observed in DRG obtained from STZ-induced diabetic mice

. Representative TRPV1 immunofluorescent pictures of DRG sections from control non-diabetic (a), STZ-induced diabetic hyperalgesic (b), hypoalgesic mice (c) and non-diabetic TRPV1 knock-out mice (d). . Summary graph showing increase in mean gray values of TRPV1 staining (n = 5 sections from 4 mice, p < 0.058) in hyperalgesic DRG and decrease in TRPV1 gray value in hypoalgesic diabetic mice (n = 6 sections from 4 mice, p < 0.05) as compared to control non-diabetic mice. . Percentage of TRPV1-expressing neurons in total DRG neuron was higher (n = 5 sections from 4 mice, p < 0.05) in hyperalgesia and did not change in hypoalgesic (n = 6 sections) diabetic mice as compared to age matched control non-diabetic mice. Note that TRPV1knock-out mice sections did not exhibit any TRPV1 staining serving as negative control. Number in the parenthesis represents the number of TRPV1 stained sections and the asterisk (*) represents p < 0.05. Scale bar is 50 μm.<p><b>Copyright information:</b></p><p>Taken from "Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity"</p><p>http://www.molecularpain.com/content/4/1/9</p><p>Molecular Pain 2008;4():9-9.</p><p>Published online 1 Mar 2008</p><p>PMCID:PMC2275252.</p><p></p

Changes in blood glucose level, body weight and thermal pain sensitivity in a double transgenic mice (TCR-SFE/Ins-HAD2) model of diabetes

A. By six weeks of age, double transgenic mice became diabetic (blood glucose levels >600 mg/dl) and remained high (filled circles, n = 9, p < 0.001) throughout the course of the experiment as compared to non-diabetic control (Ins-HAD2) mice (open circles, n = 6). B. Body weights of TCR-SFE/Ins-HAD2 mice remained constant (filled circles, n = 9), while control non-diabetic mice (Ins-HAD2) gained weight steadily (open circles, n = 6, p < 0.001) C. PWL measured from the age of 6 weeks to 18–19 weeks revealed three phenotypes as compared to control non-diabetic mice (Ins-HAD2) (open circles, n = 19). The first group exhibited an initial phase of hyperalgesia (open squares, n = 12, p < 0.001) followed by a phase of hypoalgesia (n = 8, p < 0.05). The second group showed no hyperalgesic phase, but became hypoalgesic (filled squares, n = 8, p < 0.001). The third group became hyperalgesic and remained hyperalgesic throughout the course of the study (filled circles, n = 12. Asterisks (*, **) represent p < 0.05 and p < 0.001, respectively.<p><b>Copyright information:</b></p><p>Taken from "Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity"</p><p>http://www.molecularpain.com/content/4/1/9</p><p>Molecular Pain 2008;4():9-9.</p><p>Published online 1 Mar 2008</p><p>PMCID:PMC2275252.</p><p></p

Changes in blood glucose level, body weight and thermal pain sensitivity in mice (Ins-HAD2) injected with STZ

A. After intraperitoneal injection of STZ, within the first week, blood glucose levels significantly increased (filled circles, n = 11, p < 0.001) and remained constant throughout the course of the experiment as compared to control non-diabetic mice (Ins-HAD2) (open circles, n = 6). B. The body weight of diabetic mice remained constant (filled circles, n = 11), but the body weight of control mice increased steadily (open circles, n = 6, p < 0.001) C. PWL of diabetic mice determined every week after injection of STZ show significant changes: exhibited a phase of hyperalgesia (filled circles; n = 33, p < 0.001) between weeks 1 and 4; a phase of hypoalgesia (filled circles; n = 8, p < 0.001) as compared to control non-diabetic mice (open circles, n = 19). Note that the number of mice is decreasing over the course of experiments because unhealthy mice were not tested further on the hot plate. Asterisks (*, **) represent p < 0.05 and p < 0.001, respectively.<p><b>Copyright information:</b></p><p>Taken from "Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity"</p><p>http://www.molecularpain.com/content/4/1/9</p><p>Molecular Pain 2008;4():9-9.</p><p>Published online 1 Mar 2008</p><p>PMCID:PMC2275252.</p><p></p

Changes in blood glucose level, body weight and thermal pain sensitivity in TRPV1 knock-out mice (B6

129S4-/J) injected with STZ. A. After intraperitoneal injection of STZ, within the first week, blood glucose level significantly increased (filled squares, n = 14, p < 0.001) and remained constant throughout the course of the experiment as compared to non-diabetic TRPV1 knock-out mice (open squares, n = 6) or the background strain of TRPV1 knock-out mice (C57BL/6J) (open circles n = 15). B. The body weight of TRPV1 knock-out diabetic mice remained constant (filled squares, n = 14), but the body weight of non-diabetic knock-out mice increased steadily (open squares, n = 6, p < 0.001). C. PWL of TRPV1 knock-out diabetic mice, determined every week did not show any significant change (filled squares, n = 14) as compared to control non-diabetic TRPV1 knock-out mice (open squares, n = 6) and the background strain of TRPV1 knock-out mice (open circles n = 15). Note that PWL is significantly higher in TRPV1 knock-out mice as compared to the background strain. Asterisk (**) represents p < 0.001.<p><b>Copyright information:</b></p><p>Taken from "Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity"</p><p>http://www.molecularpain.com/content/4/1/9</p><p>Molecular Pain 2008;4():9-9.</p><p>Published online 1 Mar 2008</p><p>PMCID:PMC2275252.</p><p></p

Altered TRPV1 staining in paw skin tissue obtained from STZ-induced diabetic mice

. Representative TRPV1 immunofluorescent pictures of paw skin sections from control non-diabetic (a), STZ-induced diabetic hyperalgesic (b), hypoalgesic mice (c) and non-diabetic TRPV1 knock-out mice (d). Arrows indicate the TRPV1-expressing fibers in dermis (De). Background staining was consistently observed in the epidermis (Ep) of all sections including TRPV1 knock-out mice. . Summary graph showing increased (n = 8 sections from 4 mice, p < 0.05) and decreased (n = 9 sections, p < 0.05) mean gray values of TRPV1 staining in diabetic hyperalgesic and hypoalgesic fibers of the paw dermis layer as compared with control non-diabetic mice (n = 8 sections from 4 mice). Number in the parenthesis represents the number of TRPV1 stained sections and the asterisk (*) represents p < 0.05. Scale bar is 50 μm.<p><b>Copyright information:</b></p><p>Taken from "Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity"</p><p>http://www.molecularpain.com/content/4/1/9</p><p>Molecular Pain 2008;4():9-9.</p><p>Published online 1 Mar 2008</p><p>PMCID:PMC2275252.</p><p></p