Suppressing PKC-dependent membrane P2X3 receptor upregulation in dorsal root ganglia mediated electroacupuncture analgesia in rat painful diabetic neuropathy

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 PKCdependent membrane P2X3 upregulation in DRG. EA at low frequency is a valuable approach for PDN control.

P2X3 receptors contribute to muscle pain induced by static contraction by a mechanism dependent on neutrophil migration

“…This is because both peripheral (muscle) and central (intrathecal) blockade of P2X3 receptors prevented the static contractioninduced mechanical muscle hyperalgesia. It is widely known that P2X3 receptors are involved in pain signaling of different etiologies and in different tissues, such as neuropathic (partial sciatic ligation and chronic constriction injury) and inflammatory (complete Freund's adjuvant-CFA, carrageenan, formalin-persistent phase) pain in subcutaneous tissue [13,22,41], painful diabetic neuropathy [42], cancer-induced bone pain [43], endometriosis pain [44], articular hyperalgesia [19,45], and visceral pain (colorectal distension, acetic acidinduced abdominal constriction, and trinitrobenzene sulphonic acid colitis) [46,47]. Similar to subcutaneous tissue [22] and knee joint [19] of rats, in this present study, we also demonstrated that ATP, via activation of P2X3 receptors, is an important mediator on the development but not in maintenance of muscle hyperalgesia, since A-317491 prevented the mechanical muscle hyperalgesia when administered before and 30 or 60 min after the start of static contraction, but not 30 or 60 min after the end of it.…”

Purinergic signaling as a basis of acupuncture-induced analgesia

“…Diabetic neuropathy was modeled by feeding rats with a high-fat and high-sugar diet for 5 weeks plus injecting once streptozocin [43]. Streptozocin injection alone would primarily damage the pancreas only (diabetes type 1), while in combination with the diet used, it caused long-lasting hyperglycemia and histological injury to the sciatic nerve as well (diabetes type 2).…”

Non-pharmacologic treatments for symptoms of diabetic peripheral neuropathy: a systematic review – methodological issues are a matter for concern

“…Animal experiments proved that protein kinase C (PKC)-mediated dorsal root ganglia (DRG) P2X3 receptor upregulation is a significant mechanism of PDN [9][10][11] . EA plays an analgesic role by inhibiting the upregulation of PKC-dependent membrane P2X3 in DRG 12 . To our knowledge, a systematic review about the effectiveness of manual acupuncture for treatment of DPN included 25 randomized control trials (RCTs) involving 1649 participants which were published in Chinese 3 .…”