Hyperalgesia AMPA

Emerging evidence has implicated an important role of synapse-associated protein-97 (SAP97)-regulated GluA1-containing AMPARs membrane trafficking in cocaine restate and in contextual episodic memory of schizophrenia. Herein, we investigated the role of SAP97 in neuropathic pain following lumbar 5 spinal nerve transection (SNT) in rats. Our results showed that SNT led to upregulation of SAP97, enhanced the interaction between SAP97 and GluA1, and increased GluA1-containing AMPARs membrane trafficking in the dorsal horn...

Methylglyoxal (MGO), a highly reactive dicarbonyl metabolite of glucose primarily formed during the glycolytic pathway, is a precursor of advanced glycation end-products (AGEs). Recently, numerous studies have shown that MGO accumulation can cause pain and hyperalgesia. However, the mechanism through which MGO induces pain in the spinal dorsal horn remains unclear. The present study investigated the effect of MGO on spontaneous excitatory postsynaptic currents (sEPSC) in rat spinal dorsal horn neurons using blind whole-cell patch-clamp recording...

The brain consists of the left and right cerebral hemispheres and both are connected by callosal projections. Less is known about the basic mechanism of this cortical-cortical connection and its functional importance. Here we investigate the cortical-cortical connection between the bilateral anterior cingulate cortex (ACC) by using the classic electrophysiological and optogenetic approach. We find that there is a direct synaptic projection from one side ACC to the contralateral ACC. Glutamate is the major excitatory transmitter for bilateral ACC connection, including projections to pyramidal cells in superficial (II/III) and deep (V/VI) layers of the ACC...

BACKGROUND: Perampanel, a highly selective glutamate AMPA receptor antagonist, is widely used to treat epilepsy. Since the existence of common pathophysiological features between epilepsy and migraine, the aim of this study was to investigate whether perampanel could exert an antimigraine effect. METHODS: Nitroglycerin (NTG) was used to induce a migraine model in rats, and the model animals were pretreatment with 50 μg/kg and 100 μg/kg perampanel. The expression of pituitary adenylate-cyclase-activating polypeptide (PACAP) was quantified by western blot and quantitative real-time PCR in the trigeminal ganglion, and rat-specific enzyme-linked immunosorbent assay in serum...

Diseases of joints are among the most frequent causes of chronic pain. In the course of joint diseases the peripheral and the central nociceptive system develop persistent hyperexcitability (peripheral and central sensitization). This review addresses the mechanisms of spinal sensitization evoked by arthritis. Electrophysiological recordings in anaesthetized rats from spinal cord neurons with knee input in a model of acute arthritis showed that acute spinal sensitization is dependent on spinal glutamate receptors (AMPA, NMDA and metabotropic glutamate receptors) and supported by spinal actions of neuropeptides such as neurokinins and CGRP, by prostaglandins, and by proinflammatory cytokines...

Opioids are commonly prescribed for pain despite growing evidence of their low efficacy in the treatment of chronic inflammatory pain and the high potential for misuse. There is a clear need to investigate non-opioid alternatives for the treatment of pain. In the present study, we tested the hypothesis that acute and repeated dopamine agonist treatment would attenuate mechanical hypersensitivity in male Long-Evans rats experiencing chronic inflammatory pain. We used two clinically available therapeutics, l-DOPA (precursor of dopamine biosynthesis) and pramipexole (dopamine D2/3 receptor agonist), to examine the functional role of dopamine signaling on mechanical hypersensitivity using an animal model of chronic inflammatory pain (complete Freund's adjuvant, CFA)...

Bone cancer pain (BCP) seriously affects the quality of life; however, due to its complex mechanism, the clinical treatment was unsatisfactory. Recent studies have showed several Rac-specific guanine nucleotide exchange factors (GEFs) that affect development and structure of neuronal processes play a vital role in the regulation of chronic pain. P-Rex2 is one of GEFs that regulate spine density, and the present study was performed to examine the effect of P-Rex2 on the development of BCP. Tumor cells implantation induced the mechanical hyperalgesia, which was accompanied by an increase in spinal protein P-Rex2, phosphorylated Rac1 (p-Rac1) and phosphorylated GluR1 (p-GluR1), and number of spines...

BACKGROUND: Pulsed radiofrequency (PRF) treatment uses low energy, short pulsations to modulate tissue characteristics. PRF treatment has been effective as an interventional pain management technique to treat a variety of chronic neuropathic pain (neuralgia) disorders, but a comprehensive review of its biological mechanism has not been updated in a decade. OBJECTIVES: In this literature review, we performed a literature search in PubMed to identify publications describing the mechanisms of action of pulsed radiofrequency for pain indications...

The A-kinase anchoring protein 150 (AKAP150) organizes kinases and phosphatases to regulate AMPA receptors (AMPARs) that are pivotal for synaptic plasticity. AKAP150 itself undergoes S-palmitoylation. However, the roles of AKAP150 and its palmitoylation in spinal nociceptive processing remain unknown. In this study, we found that intraplantar injection of complete Freund's adjuvant (CFA) significantly increased the synaptic expression of AKAP150 and caused a reorganization of AKAP150 signaling complex in spinal dorsal horn...

Complex Regional Pain Syndrome (CRPS) is a musculoskeletal pain condition that often develops after limb injury and/or immobilization. Although the exact mechanisms underlying CRPS are unknown, the syndrome is associated with central and autonomic nervous system dysregulation and peripheral hyperalgesia symptoms. These symptoms also manifest in alcoholic neuropathy, suggesting that the two conditions may be pathophysiologically accretive. Interestingly, people assigned female at birth (AFAB) appear to be more sensitive to both CRPS and alcoholic neuropathy...

Pain is composed of both physiological and affective/emotional components which potentiate one another. In addition, exposure to stress modulates pain and affective behaviors including, anxiety-like behavior and/or depression-like behaviors. Indeed, chronic exposure to stress has been known to enhance stress-induced hyperalgesia (SIH). The anterior cingulate cortex (ACC) is critically involved in pain sensation and emotions. Animal models of chronic pain, but not acute nociception have been found to induce synaptic plasticity on glutamatergic and GABAergic transmission in the rodent ACC...

The mechanisms underlying postoperative pain differ from the inflammatory or neuropathic pain. Previous studies have demonstrated that intrathecal α-amino-3-hydroxy-5-methy-4-isoxazole propionate (AMPA) -kainate (KA) receptor antagonist inhibits the guarding pain behavior and mechanical hyperalgesia, indicating a critical role of spinal KA receptors in postoperative pain hypersensitivity. However, how the functional regulations of spinal KA receptor subunits are involved in the postoperative pain hypersensitivity remains elusive...

The mechanism underlying the high incidence of remifentanil-induced postoperative hyperalgesia is unclear. Also, no effective prevention method exists. Inflammatory pain-related studies showed that P2X4 purinergic receptors (P2X4Rs) in the dorsal horn of the spinal cord and dorsal root ganglia are essential for maintaining allodynia caused by inflammation. However, little is known about its role in opioid-induced hyperalgesia. This study aimed to determine the role of P2X4R and related signaling pathways in the remifentanil-induced postoperative hyperalgesia (RIH) model...

Pain experience can change the central processing of nociceptive inputs, resulting in persistent allodynia and hyperalgesia. However, the underlying circuit mechanisms remain underexplored. Here, we focus on pain-induced remodeling of the projection from the mediodorsal thalamus (MD) to the anterior cingulate cortex (ACC), a projection that relays spinal nociceptive input for central processing. Using optogenetics combined with slice electrophysiology, we detected in male mice that 7 days of chronic constriction injury (CCI; achieved by loose ligation of the sciatic nerve) generated AMPA receptor (AMPAR)-silent glutamatergic synapses within the contralateral MD-to-ACC projection...

Chronic pain is one of the serious conditions that affect human health and remains cure still remains a serious challenge as the molecular mechanism remains largely unclear. Here, we used label-free proteomics to identify potential target proteins that regulate peripheral inflammatory pain and reveal its mechanism of action. Inflammation in peripheral tissue was induced by injecting complete Freund's adjuvant (CFA) into rat hind paw. A proteomic method was adopted to compare the spinal dorsal horn (SDH) in peripheral inflammatory pain (PIP) model rats with controls...

Menthol, which acts as an agonist for transient receptor potential melastatin 8 (TRPM8), has complex effects on nociceptive transmission, including pain relief and hyperalgesia. Here, we addressed the effects of menthol on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs, respectively) in medullary dorsal horn neurons, using a whole-cell patch-clamp technique. Menthol significantly increased sEPSC frequency, in a concentration-dependent manner, without affecting current amplitudes...

Gut inflammation or injury causes intestinal hypersensitivity (IHS) and hyperalgesia, which can persist after the initiating pathology resolves, are often referred to somatic regions and exacerbated by psychological stress, anxiety or depression, suggesting the involvement of both the spinal cord and the brain. The supraspinal mechanisms of IHS remain to be fully elucidated, however, over the last decades the series of intestinal pathology-associated neuroplastic changes in the brain has been revealed, being potentially responsible for the phenomenon...

Acupuncture has been used to treat a variety of illness and involves the insertion and manipulation of needles into specific points on the body (termed "acupoints"). It has been suggested that acupoints are not merely discrete, static points, but can be dynamically changed according to the pathological state of internal organs. We investigated in a rat model of mustard oil (MO)-induced visceral hyperalgesia whether the number and size of acupoints were modified according to the severity of the colonic pain, and whether the changes were associated with enhanced activity of the spinal dorsal horn...

BACKGROUND: The burden of neuropathic pain is growing worldwide. Recent studies recapitulate the requirement for AMPA receptor in excitatory synaptic plasticity underlying pain-related syndromes. Netrin-1 and its receptor deleted in colorectal cancer (DCC) are fundamental for AMPA receptor dependent synaptic transmission. Phosphatidylinositol 4-kinase IIa (Pi4KIIa) mediates post-synaptic insertion of AMPA receptor in neuropathic disorders. This study investigates whether netrin-1 and Pi4KIIa regulate peripheral nerve injury-induced neuropathic pain...

Exogenous cannabinoid receptor agonists are clinically effective for treating chronic pain but frequently cause side effects in the central nervous system. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide, an endogenous cannabinoid agonist. 3-Pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477) is a potent and selective FAAH inhibitor that is orally active and able to increase the brain anandamide level and is effective in rat models of neuropathic and osteoarthritis pain without causing motor coordination deficits...