Decreased Endomorphin-2 and μ-Opioid Receptor in the Spinal Cord Are Associated with Painful Diabetic Neuropathy

Abstract

Painful diabetic neuropathy (PDN) is one of the most common complications in the early stage of diabetes mellitus (DM). Endomorphin-2 (EM2) selectively activates the μ-opioid receptor (MOR) and subsequently induces antinociceptive effects in the spinal dorsal horn. However, the effects of EM2-MOR in PDN have not yet been clarified in the spinal dorsal horn. Therefore, we aimed to explore the role of EM2-MOR in the pathogenesis of PDN. The main findings were the following: (1) streptozotocin (STZ)-induced diabetic rats exhibited hyperglycemia, body weight loss and mechanical allodynia; (2) in the spinal dorsal horn, the expression levels of EM2 and MOR decreased in diabetic rats; (3) EM2 protein concentrations decreased in the brain, lumbar spinal cord and cerebrospinal fluid (CSF) in diabetic rats but were unchanged in the plasma; (4) the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) was significantly higher in diabetic rats than in control rats; and (5) intrathecal injection of EM2 for 14 days in the early stage of PDN partially alleviated mechanical allodynia and reduced MOR expression in diabetic rats. Our results demonstrate that the EM2-MOR signal may be involved in the early stage of PDN.

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

“…The current experimental models of PDN are usually made by a single large injection of STZ due to the convenient induction of hyperglycemia [32][33][34]. Due to the selective destruction of pancreatic beta cells, these models are characteristic of rapid onset, weight loss, and insulin deficiency, which can well represent type 1 diabetes, but fail to mimic the pathological process of type 2 diabetes, the predominant subtype of diabetes nowadays, like insulin resistance.…”

Endomorphin-2 Inhibits the Activity of the Spinoparabrachial Projection Neuron through Presynaptic Mechanisms in the Spinal Dorsal Horn in Rats

“…To investigate whether EM2 could change the intrinsic properties of TMR-labeled PNs, the single action potentials (APs) at the threshold and firing patterns (Fig. 5), we use EM2 (3 µM) bath application into the ACSF following our previous studies [20, 31]. No changes were found in the firing pattern test, where EM2 did not change the spike number in most of the recorded TMR-labeled PNs (n = 15, from 8 rats, F (1,70) =1.64, P =0.16, two-way repeated measures ANOVA).…”

“…administration of EM2 in the tail-flick, paw-withdrawal, tail pressure and flexor-reflex tests on adult rodents [10, 14-18]. Moreover, it has also been demonstrated that a reduction of EM2 is involved in the chemotherapy-induced neuropathic pain, cancer-induced bone pain, thermal hyperalgesia and inflammatory pain in ovariectomized female rats and painful diabetic neuropathy [14, 17, 19, 20]. However, the underlying mechanisms for these analgesic effect of EM2 in the SDH primarily focused on the morphological and functional studies of the substantia gelatinosa (SG, lamina II) interneurons.…”

Endomorphins: Promising Endogenous Opioid Peptides for the Development of Novel Analgesics

“…Impairment in the endogenous opioid analgesia system mediated by EM2 via MOR might be involved during the early stage of the PDN [98]. Intracerebroventricular injection of EMs could improve PDN [99].…”

“…Intracerebroventricular injection of EMs could improve PDN [99]. This down-regulation of endogenous antinociception may be due to the decreased inhibition of SP signalling resulting from the decreased presynaptic EM2 and MOR expression [94,98].…”