Abstract
Painful diabetic neuropathy (PDN) is a common and troublesome diabetes complication. Protein kinase C (PKC)-mediated dorsal root ganglia (DRG) P2X3 receptor upregulation is one important mechanism underlying PDN. Accumulating evidence demonstrated that electroacupuncture (EA) at low frequency could effectively attenuate neuropathic pain. Our previous study showed that 2-Hz EA could relieve pain well in PDN. The study aimed to investigate whether 2-Hz EA relieves pain in PDN through suppressing PKC-mediated DRG P2X3 receptor upregulation. A 7-week feeding of high-fat and high-sugar diet plus a single injection of streptozotocin (STZ) in a dose of 35 mg/kg after a 5-week feeding of the diet successfully induced type 2 PDN in rats as revealed by the elevated body weight, fasting blood glucose, fasting insulin and insulin resistance, and the reduced paw withdrawal threshold (PWT), as well as the destructive ultrastructural change of sciatic nerve. DRG plasma membrane P2X3 receptor level and DRG PKC expression were elevated. Two-hertz EA failed to improve peripheral neuropathy; however, it reduced PWT, DRG plasma membrane P2X3 receptor level, and DRG PKC expression in PDN rats. Intraperitoneal administration of P2X3 receptor agonist αβ-meATP or PKC activator phorbol 12-myristate 13-acetate (PMA) blocked 2-Hz EA analgesia. Furthermore, PMA administration increased DRG plasma membrane P2X3 receptor level in PDN rats subject to 2-Hz EA treatment. These findings together indicated that the analgesic effect of EA in PDN is mediated by suppressing PKC-dependent membrane P2X3 upregulation in DRG. EA at low frequency is a valuable approach for PDN control.
Highlights
Painful diabetic neuropathy (PDN) is a common and troublesome diabetes complication and occurs in ~ 20% of people with diabetes [1]
After being fed with the diet composed of 72.5% normal diet, 10% lard, 10% sucrose, 2% cholesterol, 0.5% sodium cholate, and 5% yolk powder for 5 weeks, rats’ body weight, fasting insulin (FINS), and insulin resistance (IR) were significantly increased as compared to those in the control group (P < 0.01, respectively) (Fig. 1a–d)
The present study investigated whether 2-Hz EA exerted analgesic effect on PDN rats by suppressing dorsal root ganglia (DRG) P2X3 receptor through Protein kinase C (PKC) pathway
Summary
Painful diabetic neuropathy (PDN) is a common and troublesome diabetes complication and occurs in ~ 20% of people with diabetes [1]. Studies show that several ion channels and receptors in dorsal root ganglia (DRG) are dysregulated in PDN, which make a contribution to sensitization of pain responses by enhancing excitability of nociceptor [3,4,5,6]. The P2X3 receptor is an important transducer of nociceptive stimuli and altered P2X3 receptor after nerve injury contributes to neuropathic pain hypersensitivity [10,11,12,13]. Upregulation of P2X3 receptor in DRG plays an important role in the development of PDN [4, 14, 15]. Many studies which employed pharmacological methods have shown the important roles of the PKC family in the modulation of pain [16]. Whether the upregulation of DRG P2X3 receptor in PDN could be mediated by PKC has not yet been identified
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