AMPAkines and morphine provide complementary analgesia

Sun, Yongjun; Liu, Kevin; Martinez, Erik; Dale, Jahrane; Huang, Dong; Wang, Jing

doi:10.1016/j.bbr.2017.07.020

Cited by 17 publications

(11 citation statements)

References 37 publications

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“…In addition, administration of drinking water containing d -Asp, a precursor of endogenous NMDA and a putative agonist at NMDA receptors, reduces mechanical allodynia, improves cognition and motor coordination, and increases social interaction in mice with neuropathic pain [ 52 ]. Direct injection of AMPAkines, which enhance glutamate signaling via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors into the PFC, results in analgesia and potentiates morphine analgesia [ 53 ]. Unilateral microinjection of glutamate into the ventrolateral PFC of rats depresses the nociceptive tail flick reflex, whereas bilateral microinjections of GABA into the ventrolateral regions of the PAG eliminates this effect [ 54 ].…”

Section: Neurochemistry Of the Pfc Related To Painmentioning

confidence: 99%

Role of the Prefrontal Cortex in Pain Processing

2018

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The prefrontal cortex (PFC) is not only important in executive functions, but also pain processing. The latter is dependent on its connections to other areas of the cerebral neocortex, hippocampus, periaqueductal gray (PAG), thalamus, amygdala, and basal nuclei. Changes in neurotransmitters, gene expression, glial cells, and neuroinflammation occur in the PFC during acute and chronic pain, that result in alterations to its structure, activity, and connectivity. The medial PFC (mPFC) could serve dual, opposing roles in pain: (1) it mediates antinociceptive effects, due to its connections with other cortical areas, and as the main source of cortical afferents to the PAG for modulation of pain. This is a 'loop' where, on one side, a sensory stimulus is transformed into a perceptual signal through high brain processing activity, and perceptual activity is then utilized to control the flow of afferent sensory stimuli at their entrance (dorsal horn) to the CNS. (2) It could induce pain chronification via its corticostriatal projection, possibly depending on the level of dopamine receptor activation (or lack of) in the ventral tegmental area-nucleus accumbens reward pathway. The PFC is involved in biopsychosocial pain management. This includes repetitive transcranial magnetic stimulation, transcranial direct current stimulation, antidepressants, acupuncture, cognitive behavioral therapy, mindfulness, music, exercise, partner support, empathy, meditation, and prayer. Studies demonstrate the role of the PFC during placebo analgesia, and in establishing links between pain and depression, anxiety, and loss of cognition. In particular, losses in PFC grey matter are often reversible after successful treatment of chronic pain.

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Section: Neurochemistry Of the Pfc Related To Painmentioning

confidence: 99%

Role of the Prefrontal Cortex in Pain Processing

2018

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“…Furthermore, AMPAkines such as CX546 have been shown to prevent sedative-induced synaptic deficits in the brain [ 64 ]. Importantly, previous studies have shown that AMPAkines have anti-nociceptive properties in acute incisional and chronic pain conditions [ 39 , 40 , 65 ], and that potentiation of the postsynaptic function of the NAc appears to be crucial for these properties [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

AMPAkines potentiate the corticostriatal pathway to reduce acute and chronic pain

et al. 2021

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The corticostriatal circuit plays an important role in the regulation of reward- and aversion-types of behaviors. Specifically, the projection from the prelimbic cortex (PL) to the nucleus accumbens (NAc) has been shown to regulate sensory and affective aspects of pain in a number of rodent models. Previous studies have shown that enhancement of glutamate signaling through the NAc by AMPAkines, a class of agents that specifically potentiate the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, reduces acute and persistent pain. However, it is not known whether postsynaptic potentiation of the NAc with these agents can achieve the full anti-nociceptive effects of PL activation. Here we compared the impact of AMPAkine treatment in the NAc with optogenetic activation of the PL on pain behaviors in rats. We found that not only does AMPAkine treatment partially reconstitute the PL inhibition of sensory withdrawals, it fully occludes the effect of the PL on reducing the aversive component of pain. These results indicate that the NAc is likely one of the key targets for the PL, especially in the regulation of pain aversion. Furthermore, our results lend support for neuromodulation or pharmacological activation of the corticostriatal circuit as an important analgesic approach.

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“…In addition, administration of CX546 into nucleus accumbens (NAc) provided antinociceptive effect in paw incision (PI) model of acute pain and inhibited persistent postoperative pain from the SNI model (Su et al, 2016). When injected locally into the prefrontal cortex (PFC), CX546 also reveal synergistic effect to morphine analgesia (Sun et al, 2017). The results indicated that analgesia effect of CX546 might be involved in the acting through AMPA receptors in the NAc and PFC.…”

Section: Discussionmentioning

confidence: 99%

The Impact and Mechanism of a Novel Allosteric AMPA Receptor Modulator LCX001 on Protection Against Respiratory Depression in Rodents

Dai¹,

Gao²,

Xiao³

et al. 2019

Front. Pharmacol.

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Analgesics and sedative hypnotics in clinical use often give rise to significant side effects, particularly respiratory depression. For emergency use, specific antagonists are currently administered to counteract respiratory depression. However, antagonists are often short-lasting and eliminate drug generated analgesia. To resolve this issue, novel positive AMPA modulators, LCX001, was tested to alleviate respiratory depression triggered by different drugs. The acetic acid writhing and hot-plate test were conducted to evaluate analgesic effect of LCX001. Binding assay, whole-cell recording, live cell imaging, and Ca 2+ imaging were used to clarify mechanism and impact of LCX001 on respiratory protection. Results showed that LCX001 effectively rescued and prevented opioid (fentanyl and TH-030418), propofol, and pentobarbital-induced respiratory depression by strengthening respiratory frequency and minute ventilation. The acetic acid writhing test and hot-plate test revealed potent anti-nociceptive efficacy of LCX001, in contrast to other typical ampakines that did not affect analgesia. Furthermore, LCX001 potentiated [ 3 H]AMPA and L-glutamate binding affinity to AMPA receptors, and facilitated glutamate-evoked inward currents in HEK293 cells stably expressing GluA2(R). LCX001 had a typical positive modulatory impact on AMPAR-mediated function. Importantly, application of LCX001 generated a significant increase in GluA2(R) surface expression, and restrained opioid-induced abnormal intracellular Ca 2+ load, which might participate in breathing modulation. Our study improves therapeutic interventions for the treatment of drug induced respiratory depression, and increases understanding of potential mechanism of AMPA receptor modulators.

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AMPAkines and morphine provide complementary analgesia

Cited by 17 publications

References 37 publications

Role of the Prefrontal Cortex in Pain Processing

Role of the Prefrontal Cortex in Pain Processing

AMPAkines potentiate the corticostriatal pathway to reduce acute and chronic pain

The Impact and Mechanism of a Novel Allosteric AMPA Receptor Modulator LCX001 on Protection Against Respiratory Depression in Rodents

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