Abstract
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.
Highlights
Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes mellitus [1]
Changes in blood glucose level, body weight and thermal pain sensitivity in mice injected with STZ STZ is toxic to pancreatic beta cells and is commonly used to induce type 1 diabetes in rodents for the study of DPN because disease induction is both rapid and reliable
Hyperalgesia was followed by a second phase of apparently normal paw withdrawal latency (PWL) and a final phase of hypoalgesia beginning at week 6 (Fig. 1C)
Summary
Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes mellitus [1]. Symptoms of this debilitating condition include progressive loss of thermal and tactile pain sensation [2,3]. Most individuals with diabetic neuropathy experience reduced perception, a fraction (~10%) experience painful symptoms [2]. Results from the Diabetes Control and Complications Trial [4] show that intensive glycemic control for 5 years reduces the incidence of neuropathy by 60% in individuals with T1D, suggesting that dysregulated glucose metabolism contributes to neuropathy. Sensory neuropathy can be detected in some individuals who have impaired glucose (page number not for citation purposes)
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