Reduction of prefrontal purinergic signaling is necessary for the analgesic effect of morphine

Abstract

Summary Morphine is commonly used to relieve moderate to severe pain, but repeated doses cause opioid tolerance. Here, we used ATP sensor and fiber photometry to detect prefrontal ATP level. It showed that prefrontal ATP level decreased after morphine injection and the event amplitude tended to decrease with continuous morphine exposure. Morphine had little effect on prefrontal ATP due to its tolerance. Therefore, we hypothesized that the analgesic effect of morphine might be related to ATP in the medial prefrontal cortex (mPFC). Moreover, local infusion of ATP partially antagonized morphine analgesia. Then we found that inhibiting P2X7R in the mPFC mimicked morphine analgesia. In morphine-tolerant mice, pretreatment with P2X4R or P2X7R antagonists in the mPFC enhanced analgesic effect. Our findings suggest that reduction of prefrontal purinergic signaling is necessary for the morphine analgesia, which help elucidate the mechanism of morphine analgesia and may lead to the development of new clinical treatments for neuropathic pain.

Purified Serum IgG from a Patient with Anti-IgLON5 Antibody Cause Long-Term Movement Disorders with Impaired Dopaminergic Pathways in Mice

“…Daily stereotactic injections of purified patient IgG or control IgG were performed over a period of 7 days into the SNc of C57BL/6 male mice [ 19 , 20 , 21 ]. The mice were adequately anesthetized with a mixture of 1.5% isoflurane and oxygen, and their heads were fixed onto a stereotactic apparatus.…”

Microglial inflammation modulates opioid analgesic tolerance

“…Intrathecal administration of P2X4 receptor antisense oligonucleotide successfully blocked the development of morphine anti‐nociceptive tolerance in rats (Horvath et al, 2010). In addition to the spinal effects, more recent evidence indicates that antagonizing P2X7 and P2X4 receptors in the medial prefrontal cortex enhances morphine analgesia in tolerant mice (Zeng et al, 2021). Therefore, blockade of purinergic P2X7 and P2X4 receptors may represent additional viable targets for reduction of morphine analgesic tolerance through inhibition of microglial activities.…”

Excitatory and inhibitory neuronal signaling in inflammatory and diabetic neuropathic pain

“…Peripheral mediators produced at the site of injured tissue include serotonin (5-HT), kinins, histamine, nerve growth factors (NGF), adenosine triphosphate (ATP), prostaglandin (PG), glutamate, leukotrienes, nitric oxide (NO), norepinephrine and protons (Yam et al 2018 ). Peripheral terminals respond to noxious stimuli through ion channels such as transient receptor potential (TRP) channels (Malko et al 2019 ; Rosenbaum et al 2022 ), acid sensing ion channels (ASIC, (Wemmie et al 2013 )), hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Lainez et al 2019 ), ATP gated P2X receptors (Ulmann et al 2008 ; Zeng et al 2021 ) and G protein-coupled receptors (GPCRs Li et al 2017a , b ; Li et al 2017a , b ; Stone and Molliver 2009 )), e.g. bradykinin (BK), and neurokinin (NK) receptors which modulate ion channels and intracellular signaling pathways (Fig.…”