Increased Nociceptive Responses in Streptozotocin-Induced Diabetic Rats and the Related Expression of Spinal NR2B Subunit of N-Methyl-D-Aspartate Receptors

Abstract

Background This study investigated the role of NR2B in a modulated pain process in the painful diabetic neuropathy (PDN) rat using various pain stimuli. Methods Thirty-two Sprague-Dawley male rats were randomly allocated into four groups (n=8): control, diabetes mellitus (DM) rats and diabetic rats treated with ifenprodil at a lower dose (0.5 µg/day) (I 0.5) or higher dose (1.0 µg/day) (I 1.0). DM was induced by a single injection of streptozotocin at 60 mg/kg on day 0 of experimentation. Diabetic status was assessed on day 3 of the experimentation. The responses on both tactile and thermal stimuli were assessed on day 0 (baseline), day 14 (pre-intervention), and day 22 (post-intervention). Ifenprodil was given intrathecally for 7 days from day 15 until day 21. On day 23, 5% formalin was injected into the rats' hind paw and the nociceptive responses were recorded for 1 hour. The rats were sacrificed 72 hours post-formalin injection and an analysis of the spinal NR2B expression was performed. Results DM rats showed a significant reduction in pain threshold in response to the tactile and thermal stimuli and higher nociceptive response during the formalin test accompanied by the higher expression of phosphorylated spinal NR2B in both sides of the spinal cord. Ifenprodil treatment for both doses showed anti-allodynic and anti-nociceptive effects with lower expression of phosphorylated and total spinal NR2B. Conclusion We suggest that the pain process in the streptozotocin-induced diabetic rat that has been modulated is associated with the higher phosphorylation of the spinal NR2B expression in the development of PDN, which is similar to other models of neuropathic rats.

N-Acetylcysteine causes analgesia in a mouse model of painful diabetic neuropathy

“…51 The mGlu2-mediated inhibition of glutamate release will restrain the activation of postsynaptic glutamate receptors which are involved in mechanisms of nociceptive sensitization, such as AMPA, NMDA, and mGlu5 receptors. [52][53][54] On the other side of the coin, the glutamate secreted by the cystine/glutamate antiporter might activate extrasynaptic GluN2Bcontaining NMDA receptor and mGlu5 receptors. STZ-induced neuropathic pain is associated with an enhanced phosphorylation of the GluN2B (NR2B) subunit of NMDA receptors and is sensitive to GluN2Bcontaining NMDA receptor blockade.…”

“…STZ-induced neuropathic pain is associated with an enhanced phosphorylation of the GluN2B (NR2B) subunit of NMDA receptors and is sensitive to GluN2B-containing NMDA receptor blockade. 54 In addition, the expression of mGlu5 receptors is increased in the spinal cord of STZ-treated mice as a result of H3 histone acetylation at the Grm5 gene promoter, and activation of the histone deacetylase, sirtuin-1, normalizes the expression of mGlu5 receptors and causes analgesia. 52 To examine whether NAC restrains or facilitates the endogenous activation of NMDA and mGlu5 receptors, we used a cocktail of memantine (a fast NMDA channel blocker 55 ) and MTEP (a negative allosteric modulator of mGlu5 receptors 56 ).…”

Synthesis of oxazolo‐annulated 3‐benzazepines designed by merging two negative allosteric NMDA receptor modulators

“…The potential of ifenprodil for the treatment of drug addiction, idiopathic pulmonary fibrosis, and Covid‐19 infections is investigated in clinical trials [ 10–12 ] and, furthermore, its positive effects in animal models of Alzheimer's disease and neuropathic pain have been reported. [ 13–15 ]…”

Ifenprodil Stereoisomers: Synthesis, Absolute Configuration, and Correlation with Biological Activity

“…Ifenprodil was initially developed as an α 1 receptor antagonist for the treatment of hypertension . Later, it was found that 1 is a potent negative allosteric modulator selectively inhibiting GluN2B subunit-containing NMDA receptors. − Commercially available ifenprodil ( unlike racemate, Cerocral®), which is used in Japan as cerebral vasodilator, showed agonistic activity at σ 1 receptors as well. , Clinical trials are currently evaluating the therapeutic potential of 1 for the treatment of drug addiction, idiopathic pulmonary fibrosis (IPF), and COVID-19. − Furthermore, 1 showed positive effects in animal models of Alzheimer’s disease and neuropathic pain. − However, the selectivity of 1 over other receptors such as σ 1 , σ 2 , α 1 , 5-HT 1A , and 5-HT 2 is rather low − and depends on the configuration …”