Endomorphin-2 Inhibition of Substance P Signaling within Lamina I of the Spinal Cord Is Impaired in Diabetic Neuropathic Pain Rats.

Yun-Qing Li,Zhen-Zhen Kou,Ya-Yun Wang,Hui Li,Ting Zhang,Fa-Ping Wan,Yang Bai

doi:10.3389/fnmol.2016.00167

Abstract

Opiate analgesia in the spinal cord is impaired in diabetic neuropathic pain (DNP), but until now the reason is unknown. We hypothesized that it resulted from a decreased inhibition of substance P (SP) signaling within the dorsal horn of the spinal cord. To investigate this possibility, we evaluated the effects of endomorphin-2 (EM2), an endogenous ligand of the μ-opioid receptor (MOR), on SP release within lamina I of the spinal dorsal horn (SDH) in rats with DNP. We established the DNP rat model and compared the analgesic efficacy of EM2 between inflammation pain and DNP rat models. Behavioral results suggested that the analgesic efficacy of EM2 was compromised in the condition of painful diabetic neuropathy. Then, we measured presynaptic SP release induced by different stimulating modalities via neurokinin-1 receptor (NK1R) internalization. Although there was no significant change in basal and evoked SP release between control and DNP rats, EM2 failed to inhibit SP release by noxious mechanical and thermal stimuli in DNP but not in control and inflammation pain model. We also observed that EM2 decreased the number of FOS-positive neurons within lamina I of the SDH but did not change the amount of FOS/NK1R double-labeled neurons. Finally, we identified a remarkable decrease in MORs within the primary afferent fibers and dorsal root ganglion (DRG) neurons by Western blot (WB) and immunohistochemistry (IHC). Taken together, these data suggest that reduced presynaptic MOR expression might account for the loss of the inhibitory effect of EM2 on SP signaling, which might be one of the neurobiological foundations for decreased opioid efficacy in the treatment of DNP.

Highlights

Diabetic neuropathic pain (DNP) is one of the most prevalent complications of diabetes mellitus (DM) and takes a heavy toll on physical health and life well-being in DM patients
A dramatic thermal hyperalgesia to noxious plantar heat stimulation was observed in diabetic rats (Figure 1D)
Since previous data suggested that opioids suppressed substance P (SP) release effectively in inflammation pain (Chen et al, 2014), we evaluated neurokinin-1 receptor (NK1R) internalization in complete Freund’s adjuvant (CFA) rats as a parallel control group

Summary

Introduction

Diabetic neuropathic pain (DNP) is one of the most prevalent complications of diabetes mellitus (DM) and takes a heavy toll on physical health and life well-being in DM patients. Substance P and MOR in Diabetic Neuropathic Pain relief from high-dose opioids (Harati et al, 2000; Watson et al, 2003), the unbearable side-effects, such as sedation, respiratory depression, tolerance and opioid-induced hyperalgesia (OIH; Grider and Ackerman, 2008; Zhao et al, 2010), hampered its clinical application. Endomorphin-2 (EM2), an endogenous μ-opioid receptor (MOR) ligand, has shown remarkable analgesic properties and fewer adverse effects. Spinal administration of EM2 has been demonstrated to alleviate nociceptive behaviors in inflammatory pain (Tateyama et al, 2002; Zhao et al, 2015), cancer pain (Chen L. et al, 2015) and peripheral neuropathic pain models (Przewlocka et al, 1999). There are few reports concerning the analgesic effects of EM2 at the spinal level in the DNP model

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