Analgesic and Anti-Inflammatory Effects of Perampanel in Acute and Chronic Pain Models in Mice: Interaction With the Cannabinergic System

Abstract

Pain conditions, such as neuropathic pain (NP) and persistent inflammatory pain are therapeutically difficult to manage. Previous studies have shown the involvement of glutamate receptor in pain modulation and in particular same of these showed the key role of the AMPA ionotropic glutamate receptor subtype. Antiseizure medications (ASMs) are often used to treat this symptom, however the effect of perampanel (PER), an ASM acting as selective, non-competitive inhibitor of the AMPA receptor on the management of pain has not well been investigated yet. Here we tested the potential analgesic and anti-inflammatory effects of PER, in acute and chronic pain models. PER was given orally either in acute (5 mg/kg) or repeated administration (3 mg/kg/d for 4 days). Pain response was assessed using models of nociceptive sensitivity, visceral and inflammatory pain, and mechanical allodynia and hyperalgesia induced by chronic constriction injury to the sciatic nerve. PER significantly reduced pain perception in all behavioral tests as well as CCI-induced mechanical allodynia and hyperalgesia in acute regimen (5 mg/kg). This effect was also observed after repeated treatment using the dose of 3 mg/kg/d. The antinociceptive, antiallodynic and antihyperalgesic effects of PER were attenuated when the CB1 antagonist AM251 (1 mg/kg/i.p.) was administered before PER treatment, suggesting the involvement of the cannabinergic system. Moreover, Ex vivo analyses showed that PER significantly increased CB1 receptor expression and reduced inflammatory cytokines (i.e. TNFα, IL-1β, and IL-6) in the spinal cord. In conclusion, these results extend our knowledge on PER antinociceptive and antiallodynic effects and support the involvement of cannabinergic system on its mode of action.

Perampanel, an AMPAR antagonist, alleviates experimental intracerebral hemorrhage‑induced brain injury via necroptosis and neuroinflammation

“…Perampanel, an orally active, noncompetitive, selective AMPAR antagonist, has been widely used for the treatment of epilepsy ( 23 ). Previous studies have revealed that AMPAR antagonists are important potential neuroprotective agents in preclinical models of ischemic stroke ( 39 ), spinal cord injury ( 40 ), and traumatic brain injury ( 27 ). However, while these early studies revealed that AMPAR antagonists could minimize brain injury and neuronal death following ICH, the potential molecular mechanisms and consequent effects were not explored.…”

Nalbuphine alleviates inflammation by down-regulating NF-κB in an acute inflammatory visceral pain rat model

“…Visceral pain tends to company physical discomfort and special positions like knee flexion position in humans. Similarly, the number of writhes in a certain period reflects the degree of pain in rats and is often used in pain-model experiments [ 44 – 46 ]. Acute visceral pain like acute appendicitis tends to lead to superficial or deep hyperalgesia or allodynia [ 47 ].…”

Nalbuphine Alleviates Inflammation by Down-regulating NF-κB in an Acute Inflammatory Visceral Pain Rat Model

“…TNF-α, IL-6, IL-1β, and IL-2 are involved in many in ammatory visceral pain diseases like visceral pain after surgery, endometriosis [40,41]. Nalbuphine is applied in some clinical researches to play valid antiin ammatory and analgesic effects [42,43]. Excepting in the clinical studies, in ML's study, expressions of pro-in ammatory cytokines (IL-6, IL-1β, and TNF-α) in the spinal cord tissues were increased in visceral pain rats and inhibited by dexmedetomidine [44].…”

“…Similarly, the number of writhes in a certain period re ects the degree of pain in rats and is often used in pain-model experiments [41][42][43]. Acute visceral pain like acute appendicitis tends to lead to super cial or deep hyperalgesia or allodynia [44].…”