Long-lasting analgesia via targeted in situ repression of Na _V 1.7 in mice

Abstract

Current treatments for chronic pain rely largely on opioids despite their substantial side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in NaV1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between NaV subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of NaV1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)–dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Toward this end, we first optimized the efficiency of NaV1.7 repression in vitro in Neuro2A cells and then, by the lumbar intrathecal route, delivered both epigenome engineering 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 show effective repression of NaV1.7 in lumbar dorsal root ganglia, reduced thermal hyperalgesia in the inflammatory state, decreased tactile allodynia in the neuropathic state, and no changes in normal motor function in mice. We anticipate that this long-lasting analgesia via targeted in vivo epigenetic repression of NaV1.7 methodology we dub pain LATER, might have therapeutic potential in management of persistent pain states.

TRPV1 Responses in the Cerebellum Lobules VI, VII, VIII Using Electroacupuncture Treatment for Chronic Pain and Depression Comorbidity in a Murine Model

“…The converse over-expression of the voltage-gated sodium channels of Nav1.7 and Nav1.8 in the cerebellar lobules VI and VIII, but not in VII, suggest locational specificity, and this is similarly observed in acute pain states within the cerebellum [ 61 ]. Loss of function of the Nav1.7 leads to allodynia without other neurodevelopmental alterations such as depression, whereby repression of Nav1.7 has been associated with long-lasting analgesia [ 62 ]. Moreover, increased states of psychological stress result in increased expression of Nav1.7 and potentiate the pathogenesis of chronic pain [ 63 ].…”

A central mechanism of analgesia in mice and humans lacking the sodium channel NaV1.7

“…Close to 100% channel blockade may be required to drive the changes in opioid function responsible for analgesia (Minett et al, 2015). For intractable chronic pain, gene therapy strategies that mimic genetic loss of function will likely be required (Moreno et al, 2021).…”

Acupoint Injection of Dextrose Attenuates Chronic Inflammatory Pain In Mice Through Modulation of Transient Receptor Potential V1 Channel Expression

“…Overexpression of the voltage-gated sodium channels Nav1.7 and Nav1.8 have also been observed in the DRG and SC of acute pain model animals [29]. Conversely, suppression of Nav1.7 was associated with long-lasting analgesia [30]. Furthermore, Nav1.8 is highly expressed by nociceptive sensory afferents, and expression increases during chronic pain [31].…”