Intrathecal delivery of a palmitoylated peptide targeting Y382-384 within the P2X7 receptor alleviates neuropathic pain

Dalgarno, Rebecca; Leduc‐Pessah, Heather; Pilapil, Alexandra; Kwok, Charlie H.T.; Trang, Tuan

doi:10.1177/1744806918795793

Cited by 15 publications

(8 citation statements)

References 46 publications

(60 reference statements)

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“…This was significantly attenuated in mice previously treated with KRAB-dCas9. Spinal purine receptors have been shown to play a pivotal role in the nociceptive processing initiated by a variety of stimulus conditions including inflammatory/incisional pain and a variety of neuropathies 72,[88][89][90] . The present observations suggest that the repression of afferent Na V 1.7 expression in the nociceptor leads to a suppression of enhanced tactile sensitivity induced centrally.…”

Section: In Vivo Spinal Na V 17 Knock Downmentioning

confidence: 99%

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

Moreno

Catroli

Alemán

et al. 2019

Preprint

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One sentence summary:In situ epigenome engineering approach for genomically scarless, durable, and non-addictive management of pain. ABSTRACTCurrent treatments for chronic pain rely largely on opioids despite their unwanted side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing, with the voltage-gated sodium channel, Na V 1.7 (SCN9A), being perhaps the most promising candidate for analgesic drug development.Specifically, a hereditary loss-of-function mutation in Na V 1.7 leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence similarity between Na V subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of Na V 1.7 via genome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins as a potential treatment for chronic pain.Towards this end, we first optimized the efficiency of Na V 1.7 repression in vitro in Neuro2A cells, and then by the lumbar intrathecal route delivered both genomeengineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain and BzATP-induced pain. Our results demonstrate: one, effective repression of Na V 1.7 in lumbar dorsal root ganglia; two, reduced thermal hyperalgesia in the inflammatory state; three, decreased tactile allodynia in the neuropathic state; and four, no changes in normal motor function. We anticipate this genomically scarless and non-addictive pain amelioration approach enabling Long-lasting Analgesia via Targeted in vivo Epigenetic Repression of Nav1.7, a methodology we dub pain LATER, will have significant therapeutic potential, such as for preemptive administration in 2 anticipation of a pain stimulus (pre-operatively), or during an established chronic pain state.

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Section: In Vivo Spinal Na V 17 Knock Downmentioning

confidence: 99%

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

Moreno

Catroli

Alemán

et al. 2019

Preprint

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“…The disruption of chloride homeostasis results in enhanced excitation and diminished inhibition of spinal nociceptive output, implicated in the aberrant mechanical pain sensitivity following nerve injury (Coull et al, 2005;Mapplebeck et al, 2019;Ferrini et al, 2020). In addition, reactive microglia act through P2X7 receptors, the production of nitric oxide (NO), and the release of proinflammatory cytokines like tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and cathepsin S (CTSS) (Clark et al, 2007;Guan et al, 2016;Kobayashi et al, 2016;Kanda et al, 2017;Dalgarno et al, 2018;Mousseau et al, 2018). Thus, a myriad of microglia mechanisms involving diverse signaling pathways and pro-inflammatory cytokines (Figure 1) contribute to central sensitization underlying the aberrant nociceptive processing associated with chronic pain (Coull et al, 2005;Kawasaki et al, 2008).…”

Section: Spinal Microglia: Contributors To Chronic Painmentioning

confidence: 99%

Cannabinoids in Chronic Pain: Therapeutic Potential Through Microglia Modulation

Hoogen

Harding

Davidson

et al. 2022

Front. Neural Circuits

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Chronic pain is a complex sensory, cognitive, and emotional experience that imposes a great personal, psychological, and socioeconomic burden on patients. An estimated 1.5 billion people worldwide are afflicted with chronic pain, which is often difficult to treat and may be resistant to the potent pain-relieving effects of opioid analgesics. Attention has therefore focused on advancing new pain therapies directed at the cannabinoid system because of its key role in pain modulation. Endocannabinoids and exogenous cannabinoids exert their actions primarily through Gi/o-protein coupled cannabinoid CB1 and CB2 receptors expressed throughout the nervous system. CB1 receptors are found at key nodes along the pain pathway and their activity gates both the sensory and affective components of pain. CB2 receptors are typically expressed at low levels on microglia, astrocytes, and peripheral immune cells. In chronic pain states, there is a marked increase in CB2 expression which modulates the activity of these central and peripheral immune cells with important consequences for the surrounding pain circuitry. Growing evidence indicate that interventions targeting CB1 or CB2 receptors improve pain outcomes in a variety of preclinical pain models. In this mini-review, we will highlight recent advances in understanding how cannabinoids modulate microglia function and its implications for cannabinoid-mediated analgesia, focusing on microglia-neuron interactions within the spinal nociceptive circuitry.

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“…(2) In P2X7R deficient mice, the LPS-induced release of IL-1β from the peritoneal lavage of macrophages was abrogated [ 43 ] and the intrathecal LPS-induced mechanical hypersensitivity in the hind-paws was blocked [ 44 ]. (3) Both P2X7R antagonists [ 39 , 42 , 43 ] and intrathecal delivery of a palmitoylated peptide targeting Y 382-384 at the C-terminus of the P2X7R [ 45 ] alleviated neuropathic pain caused by spared nerve injury. Y 382-384 is a putative phosphorylation site that gates the potentiation of the P2X7R in a Src kinase-dependent fashion [ 46 ].…”

Section: Pain As a Sensory Quality; P2x7rs And Chronic Painmentioning

confidence: 99%

Involvement of P2X7 receptors in chronic pain disorders

Ren

Illéš

2021

Purinergic Signalling

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Chronic pain is caused by cellular damage with an obligatory inflammatory component. In response to noxious stimuli, high levels of ATP leave according to their concentration gradient, the intracellular space through discontinuities generated in the plasma membrane or diffusion through pannexin-1 hemichannels, and activate P2X7Rs localized at peripheral and central immune cells. Because of the involvement of P2X7Rs in immune functions and especially the initiation of macrophage/microglial and astrocytic secretion of cytokines, chemokines, prostaglandins, proteases, reactive oxygen, and nitrogen species as well as the excitotoxic glutamate/ATP, this receptor type has a key role in chronic pain processes. Microglia are equipped with a battery of pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) from bacterial infections or danger associated molecular patterns (DAMPs) such as ATP. The co-stimulation of these receptors leads to the activation of the NLRP3 inflammasome and interleukin-1β (IL-1β) release. In the present review, we invite you to a journey through inflammatory and neuropathic pain, primary headache, and regulation of morphine analgesic tolerance, in the pathophysiology of which P2X7Rs are centrally involved. P2X7R bearing microglia and astrocyte-like cells playing eminent roles in chronic pain will be also discussed.

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Intrathecal delivery of a palmitoylated peptide targeting Y382-384 within the P2X7 receptor alleviates neuropathic pain

Cited by 15 publications

References 46 publications

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

Cannabinoids in Chronic Pain: Therapeutic Potential Through Microglia Modulation

Involvement of P2X7 receptors in chronic pain disorders

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