Search

Diabetic neuropathic pain (DNP) plays a major role in decreased life quality of diabetes patients, however, the neural mechanisms underlying DNP remain unclear. Endomorphins are the endogenous ligands for mu-opioid receptor. There is increasing evidence implicating the involvement of spinal endomorphin-2 (EM2) in neuropathic pain. In this study, using a streptozotocin induced diabetic rat model that displayed obvious mechanical allodynia, it was found that the expression of spinal EM2 was significantly decreased in DNP rats. While intrathecal administration of exogenous EM2 attenuated mechanical allodynia in DNP rats, the mu-opioid receptor antagonist β-funaltrexamine facilitated these events. It was found that the reduction in spinal EM2 was mediated by increased activity of dipeptidylpeptidase IV, possibly as a consequence of diabetes-induced oxidative stress. Taken together, our results provide the first evidence that the reduction in the level of an endogenous opioid in primary afferents was significantly associated with DNP. This indicates that the chronic pain associated with DNP might be due to the loss of an inhibitory effect on pain signal transmission.

It has been shown that endomorphin-2-like immunoreactive (EM2-LI) neurons in dorsal root ganglion play important roles in regulating somatic information transmission. Although EM2-ergic neurons have been found in nodose ganglion (NG) which is mainly involved in transmitting visceral information into the nucleus tractus solitarii (NTS), the neurochemical phenotypes of EM2-ergic neurons have not yet been investigated. In the present study, immunofluorescent histochemical staining showed that 43.5% of the NG neurons contained EM2 and these neurons were small to medium in size. 15.2%, 27.8%, 74.4% and 25.2% of the EM2-LI NG neurons expressed substance P (SP), calcitonin gene-related peptide (CGRP), nitric oxide synthase (NOS) and vasoactive intestinal peptide (VIP), respectively. In addition, about 90.8% of EM2-LI NG neurons also contained mu-opioid receptor (MOR). EM2/MOR and EM2/SP double-labeled peripheral axons were observed in the vagal trunk. Anterograde tracing combined with immunofluorescent staining showed EM2/MOR and EM2/SP double-labeled vagal afferents in the NTS. EM2/MOR/SP and EM2/MOR/CGRP triple-labeled neurons and axons were observed in the NG. Importantly, at the ultrastructrual level, post-embedding electron microscopy revealed that EM2-LI and SP-LI gold particles coexisted in the same large dense-cored synaptic vesicles in the pre-synaptic button, while MOR-LI gold particles existed on both pre- and post-synaptic membranes in the NTS. These results suggest that EM2 in axon terminals of NG neurons might be involved in visceral information transmission and homeostatic control through modulating the release of other neurotransmitters (such as SP, CGRP, NO, VIP) via pre-synaptic MOR and through post-synaptic mechanisms in the NTS.