Endomorphin analog exhibited superiority in alleviating neuropathic hyperalgesia via weak activation of NMDA receptors

Abstract

Morphine is a key drug for the treatment of pain but its side effects limit its clinical application. MEL-0614, an endomorphin-1 analog, has fewer side effects than morphine in addition to its powerful analgesic effect. In this study, we measured the effect of morphine and MEL-0614 on hyperalgesia (7 days) and neuropathic allodynia (14 days) after thermal, mechanical, and cold stimulation. We found that after four and eight consecutive days of intrathecal administration (1, 3, and 10 nmol), morphine induced severe hyperalgesia and neuropathic allodynia, respectively. MEL-0614 did not induce hyperalgesia at low doses (1 and 3 nmol) and had a mitigating effect on morphine-induced neuropathic exacerbations in spared nerve injury mice. Hyperalgesia was blocked by Dynorphin A (1-17) antibody but not by an opioid receptor antagonist. To explore the reasons for the different results of morphine and MEL-0614, we used quantitative PCR and immunofluorescence to explore the effects of both on N-methyl-D-aspartate (NMDA) receptor subtype 2B (NR2B), microglia marker iba-1, and inflammatory mediators. After 8 days of consecutive administration, morphine (10 nmol) promoted an increase in the number of NR2B, iba-1, and inflammatory mediators in the spinal cord of mice. MEL-0614 (10 nmol) had no significant effect on these factors, and after co-administration with morphine, the expression of NR2B, iba-1, and inflammatory mediators was lower than that with morphine injection alone. Our research showed the advantage of MEL-0614 in terms of hyperalgesia and neuropathic allodynia, which may provide clinical relief of hyperalgesia and neuropathic allodynia caused by morphine.

Repeated Endomorphin Analogue MEL-0614 Reduces Tolerance and Improves Chronic Postoperative Pain without Modulating the P2X7R Signaling Pathway

“…Numerous studies have shown that the activation of microglia has a crucial role in the increase of pain, especially in terms of opioid-induced tolerance and hyperalgesia, , which fully indicated that the mechanisms of tolerance and hyperalgesia development may share many similarities. In our previous study, we found that MEL-0614 induced less hyperalgesia and had an alleviation effect on morphine-induced hyperalgesia in neuropathic pain . We further investigated whether repeated administration of morphine or MEL-0614 would induce the development of tolerance in CPSP.…”

Rosiglitazone Alleviates Mechanical Allodynia of Rats with Bone Cancer Pain through the Activation of PPAR-γ to Inhibit the NF-κB/NLRP3 Inflammatory Axis in Spinal Cord Neurons

“…During the operation, a heating blanket was used to keep the body temperature stable, and all operators skillfully performed the related surgical procedures to shorten the operation time. With reference to previous studies [ 29 , 30 ], sodium pentobarbital was prepared as a solution with a final concentration of 5 mg/ml to avoid irritation. After surgery, wounds were topically disinfected with 75% ( v / v ) ethanol, but not with systemic antibiotics, to avoid interference with experimental pharmacological treatments.…”

Spinal Nrf2 translocation may inhibit neuronal NF‐κB activation and alleviate allodynia in a rat model of bone cancer pain

“…bone cancer pain, HO-1, neuroinflammation, NF-κB, Nrf2, nuclear translocation chose the best experimental scheme and reduced the number of animals as much as possible. Referring to the previous literature (Fulas et al, 2020;Hu et al, 2017;Ma et al, 2020), sodium pentobarbital was used to anaesthetize rats. Sodium pentobarbital was finally configured to a final concentration of 5 mg/ml solution to avoid irritation.…”

“…The behavioural experiments were 6 rats per group (Ni et al, 2019), 4 rats per group for western blot (He et al, 2020) and immunofluorescence (Ni et al, 2020), 5 rats per group for real-time quantitative PCR (Mohamed et al, 2020) and enzyme-linked immunosorbent assay (Zhang et al, 2019) and 10 rats per group for computed tomography (CT) reconstruction and histological analysis of bone (Xu et al, 2019). Referring to the previous literature (Ma et al, 2020), the animals were simply randomly grouped. For example, in the Figure 1a, 52 rats were artificially numbered 1-52, and then each rat corresponded to a pseudorandom number generated by computer software on the order of 1-52.…”

“…Subsequent molecular experiments were performed by researchers who were not involved in the previous two operations. Data analysis was not blinded (Ma et al, 2020).…”