Endogenous inflammatory mediators contribute to the pathogenesis of pain by acting on nociceptors, specialized sensory neurons that detect noxious stimuli. Here, we describe a new factor mediating inflammatory pain. We show that platelet-derived growth factor (PDGF)-BB applied in vitro causes repetitive firing of dissociated nociceptor-like rat dorsal root ganglion neurons and decreased their threshold for action potential generation. Injection of PDGF-BB into the paw produced nocifensive behavior in rats and led to thermal and mechanical pain hypersensitivity. We further detailed the biophysical mechanisms of these PDGF-BB effects and show that PDGF receptor-induced inhibition of nociceptive M-current underlies PDGF-BB-mediated nociceptive hyperexcitability. Moreover, in vivo sequestration of PDGF or inhibition of the PDGF receptor attenuates acute formalin-induced inflammatory pain. Our discovery of a new pain-facilitating proinflammatory mediator, which by inhibiting M-current activates nociceptive neurons and thus contributes to inflammatory pain, improves our understanding of inflammatory pain pathophysiology and may have important clinical implications for pain treatment. © 2019 International Association for the Study of Pain.

Targeted delivery of therapeutic compounds to particular cell types such that they only affect the target cells is of great clinical importance since it can minimize undesired side effects. For example, typical chemotherapeutic treatments used in the treatment of neoplastic disorders are cytotoxic not only to cancer cells but also to most normal cells when exposed to a critical concentration of the compound. As such, many chemotherapeutics exhibit severe side effects, often prohibiting their effective use in the treatment of cancer. Here, we describe a new means for facilitated delivery of a clinically used chemotherapy compound' doxorubicin, into hepatocellular carcinoma cell line (BNL1 ME). We demonstrate that these cells express a large pore, cation non-selective transient receptor potential (TRP) channel V2. We utilized this channel to shuttle doxorubicin into BNL1 ME cells. We show that co-application of either cannabidiol (CBD) or 2-APB, the activators of TRPV2 channels, together with doxorubicin leads to significantly higher accumulation of doxorubicin in BNL1 ME cells than in BNL1 ME cells that were exposed to doxorubicin alone. Moreover, we demonstrate that sub-effective doses of doxorubicin when co-applied with either 2-APB or CBD lead to a significant decrease in the number of living BNL1 ME cell and BNL1 ME cell colonies in comparison to application of doxorubicin alone. Finally, we demonstrate that the doxorubicin-mediated cell death is significantly more potent, requiring an order of magnitude lower dose, when co-applied with CBD than with 2-APB. We suggest that CBD may have a dual effect in promoting doxorubicin-mediated cell death by facilitating the entry of doxorubicin via TRPV2 channels and preventing its clearance from the cells by inhibiting P-glycoprotein ATPase transporter. Collectively, these results provide a foundation for the use of large pore cation-non selective channels as “natural” drug delivery systems for targeting specific cell types. Copyright © 2019 Neumann-Raizel, Shilo, Lev, Mogilevsky, Katz, Shneor, Shaul, Leffler, Gabizon, Karni, Honigman and Binshtok. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.