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A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain

by Pelissier, Teresa , Whittaker, Michael R , Scheff, Nicole N , Stewart, Gregory D , Poole, Daniel P , Quinn, John F , Davis, Thomas P , Bunnett, Nigel W , Shenoy, Priyank , Lieu, TinaMarie , Lumb, Chris , Layani, Louis M , Ramírez-García, Paulina D , Truong, Nghia , Imlach, Wendy , Latorre, Rocco , Sykes, Matthew , Nowell, Cameron J , Retamal, Jeffri S , Mai, Quynh N , Khor, Song Y , Veldhuis, Nicholas A , Jensen, Dane D , Constandil, Luis , Schmidt, Brian L

in Acidification / Chronic pain / Clathrin / Drug delivery / Drug delivery systems / Dynamin / Endocytosis / Endosomes / Inflammation / Nanoparticles / Neurokinin / Neurokinin NK1 receptors / Opioids / Pain / Pain perception / pH effects / Substance P

2019

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A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain

2019

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2019

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Journal Article

A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain

Pelissier, Teresa,

Whittaker, Michael R,

Scheff, Nicole N,

Stewart, Gregory D,

Poole, Daniel P,

Quinn, John F,

Davis, Thomas P,

Bunnett, Nigel W,

Shenoy, Priyank,

Lieu, TinaMarie,

Lumb, Chris,

Layani, Louis M,

Ramírez-García, Paulina D,

Truong, Nghia,

Imlach, Wendy,

Latorre, Rocco,

Sykes, Matthew,

Nowell, Cameron J,

Retamal, Jeffri S,

Mai, Quynh N,

Khor, Song Y,

Veldhuis, Nicholas A,

Jensen, Dane D,

Constandil, Luis,

Schmidt, Brian L

2019

Overview

Nanoparticle-mediated drug delivery is especially useful for targets within endosomes because of the endosomal transport mechanisms of many nanomedicines within cells. Here, we report the design of a pH-responsive, soft polymeric nanoparticle for the targeting of acidified endosomes to precisely inhibit endosomal signalling events leading to chronic pain. In chronic pain, the substance P (SP) neurokinin 1 receptor (NK1R) redistributes from the plasma membrane to acidified endosomes, where it signals to maintain pain. Therefore, the NK1R in endosomes provides an important target for pain relief. The pH-responsive nanoparticles enter cells by clathrin- and dynamin-dependent endocytosis and accumulate in NK1R-containing endosomes. Following intrathecal injection into rodents, the nanoparticles, containing the FDA-approved NK1R antagonist aprepitant, inhibit SP-induced activation of spinal neurons and thus prevent pain transmission. Treatment with the nanoparticles leads to complete and persistent relief from nociceptive, inflammatory and neuropathic nociception and offers a much-needed non-opioid treatment option for chronic pain.

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Publisher

Nature Publishing Group

Subject

/ Drug delivery systems

/ Dynamin

/ Endocytosis