Reversal of Neuropathic Pain in Diabetes
Reversal of Neuropathic Pain in Diabetes
It has been established that CaV3.2 T-type voltage-gated calcium channels (T-channels) play a key role in the sensitized (hyperexcitable) state of nociceptive sensory neurons (nociceptors) in response to hyperglycemia associated with diabetes, which in turn can be a basis for painful symptoms of peripheral diabetic neuropathy (PDN). Unfortunately, current treatment for painful PDN has been limited by nonspecific systemic drugs with significant side effects or potential for abuse. We studied in vitro and in vivo mechanisms of plasticity of CaV3.2 T-channel in a leptin-deficient (ob/ob) mouse model of PDN. We demonstrate that posttranslational glycosylation of specific extracellular asparagine residues in CaV3.2 channels accelerates current kinetics, increases current density, and augments channel membrane expression. Importantly, deglycosylation treatment with neuraminidase inhibits native T-currents in nociceptors and in so doing completely and selectively reverses hyperalgesia in diabetic ob/ob mice without altering baseline pain responses in healthy mice. Our study describes a new mechanism for the regulation of CaV3.2 activity and suggests that modulating the glycosylation state of T-channels in nociceptors may provide a way to suppress peripheral sensitization. Understanding the details of this regulatory pathway could facilitate the development of novel specific therapies for the treatment of painful PDN.
Despite significant advances in glucose monitoring and insulin therapy, people with diabetes remain hyperglycemic during significant portions of the day, placing them at increased risk for the development of diabetes complications including peripheral diabetic neuropathy (PDN). One of the notable features of early PDN is the development of chronic neuropathic pain manifested as allodynia and hyperalgesia. Unfortunately, currently available therapies have limited efficacy or serious side effects. For example, gabapentin and pregabalin can relieve symptoms of painful PDN; however, >50% of patients using these drugs experience side effects, most notably excessive sedation, which limits their clinical use. Although opioids and nonsteroidal pain killers are also partially effective for treatment of chronic painful disorders, their long-term use is associated with side effects like gastrointestinal bleeding, tolerance, and addiction. Hence, further research to develop mechanism-specific novel pain therapies is warranted.
Recent studies have established the importance of the CaV3.2 subtype of T-channels in controlling the excitability of peripheral nociceptors in dorsal root ganglia (DRG) and supporting peripheral pain processing in animal models of PDN. Despite these interesting findings, no pharmacological approach targeting these channels has provided a significant therapeutic benefit to these patients. This is in part because the mechanisms underlying DRG T-channel plasticity in chronic pain disorders, like PDN, remain unknown. Here, we hypothesize that posttranslational modification of CaV3.2 channels in nociceptors via glycosylation contributes to painful symptoms in an animal model of PDN.
Abstract and Introduction
Abstract
It has been established that CaV3.2 T-type voltage-gated calcium channels (T-channels) play a key role in the sensitized (hyperexcitable) state of nociceptive sensory neurons (nociceptors) in response to hyperglycemia associated with diabetes, which in turn can be a basis for painful symptoms of peripheral diabetic neuropathy (PDN). Unfortunately, current treatment for painful PDN has been limited by nonspecific systemic drugs with significant side effects or potential for abuse. We studied in vitro and in vivo mechanisms of plasticity of CaV3.2 T-channel in a leptin-deficient (ob/ob) mouse model of PDN. We demonstrate that posttranslational glycosylation of specific extracellular asparagine residues in CaV3.2 channels accelerates current kinetics, increases current density, and augments channel membrane expression. Importantly, deglycosylation treatment with neuraminidase inhibits native T-currents in nociceptors and in so doing completely and selectively reverses hyperalgesia in diabetic ob/ob mice without altering baseline pain responses in healthy mice. Our study describes a new mechanism for the regulation of CaV3.2 activity and suggests that modulating the glycosylation state of T-channels in nociceptors may provide a way to suppress peripheral sensitization. Understanding the details of this regulatory pathway could facilitate the development of novel specific therapies for the treatment of painful PDN.
Introduction
Despite significant advances in glucose monitoring and insulin therapy, people with diabetes remain hyperglycemic during significant portions of the day, placing them at increased risk for the development of diabetes complications including peripheral diabetic neuropathy (PDN). One of the notable features of early PDN is the development of chronic neuropathic pain manifested as allodynia and hyperalgesia. Unfortunately, currently available therapies have limited efficacy or serious side effects. For example, gabapentin and pregabalin can relieve symptoms of painful PDN; however, >50% of patients using these drugs experience side effects, most notably excessive sedation, which limits their clinical use. Although opioids and nonsteroidal pain killers are also partially effective for treatment of chronic painful disorders, their long-term use is associated with side effects like gastrointestinal bleeding, tolerance, and addiction. Hence, further research to develop mechanism-specific novel pain therapies is warranted.
Recent studies have established the importance of the CaV3.2 subtype of T-channels in controlling the excitability of peripheral nociceptors in dorsal root ganglia (DRG) and supporting peripheral pain processing in animal models of PDN. Despite these interesting findings, no pharmacological approach targeting these channels has provided a significant therapeutic benefit to these patients. This is in part because the mechanisms underlying DRG T-channel plasticity in chronic pain disorders, like PDN, remain unknown. Here, we hypothesize that posttranslational modification of CaV3.2 channels in nociceptors via glycosylation contributes to painful symptoms in an animal model of PDN.
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