The development of painful paclitaxel-induced peripheral neuropathy (PIPN) represents a major dose-limiting side effect of paclitaxel chemotherapy. Here we report a promising effect of duvelisib (Copiktra), a novel FDA-approved PI3Kδ/γ isoform-specific inhibitor, in preventing paclitaxel-induced pain-like behavior and pronociceptive signaling in DRGs and spinal cord dorsal horn (SCDH) in rat and mouse model of PIPN. Duvelisib blocked the development of mechanical hyperalgesia in both males and females. Moreover, duvelisib prevented paclitaxel-induced sensitization of TRPV1 receptors, and increased PI3K/Akt signaling in small-diameter DRG neurons and an increase of CD68+ cells within DRGs. Specific optogenetic stimulation of inhibitory neurons combined with patch-clamp recording revealed that duvelisib inhibited paclitaxel-induced weakening of inhibitory, mainly glycinergic control on SCDH excitatory neurons. Enhanced excitatory and reduced inhibitory neurotransmission in the SCDH following PIPN was also alleviated by duvelisib application. In summary, duvelisib showed a promising ability to prevent neuropathic pain in PIPN. The potential use of our findings in human medicine may be augmented by the fact that duvelisib is an FDA-approved drug with known side effects.SIGNIFICANCE STATEMENT We show that duvelisib, a novel FDA-approved PI3Kδ/γ isoform-specific inhibitor, prevents the development of paclitaxel-induced pain-like behavior in males and females and prevents pronociceptive signaling in DRGs and spinal cord dorsal horn in rat and mouse model of paclitaxel-induced peripheral neuropathy.

Laboratory of Pain Research Institute of Physiology of the Czech Academy of Sciences Prague 142 20 Czech Republic

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Adamek P, Heles M, Palecek J (2019) Mechanical allodynia and enhanced responses to capsaicin are mediated by PI3K in a paclitaxel model of peripheral neuropathy. Neuropharmacology 146:163–174. 10.1016/j.neuropharm.2018.11.027 PubMed DOI

Allen DT, Kiernan JA (1994) Permeation of proteins from the blood into peripheral nerves and ganglia. Neuroscience 59:755–764. 10.1016/0306-4522(94)90192-9 PubMed DOI

Blair HA (2018) Duvelisib: first global approval. Drugs 78:1847–1853. 10.1007/s40265-018-1013-4 PubMed DOI

Boyette-Davis JA, Hou S, Abdi S, Dougherty PM (2018) An updated understanding of the mechanisms involved in chemotherapy-induced neuropathy. Pain Manag 8:363–375. 10.2217/pmt-2018-0020 PubMed DOI PMC

Boyle DL, Kim HR, Topolewski K, Bartok B, Firestein GS (2014) Novel phosphoinositide 3-kinase delta, gamma inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis. J Pharmacol Exp Ther 348:271–280. 10.1124/jpet.113.205955 PubMed DOI

Braz JM, Wang XD, Guan ZH, Rubenstein JL, Basbaum AI (2015) Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity. Pain 156:1084–1091. 10.1097/j.pain.0000000000000152 PubMed DOI PMC

Brewer AL, Shirachi DY, Quock RM, Craft RM (2020) Effect of hyperbaric oxygen on chemotherapy-induced neuropathy in male and female rats. Behav Pharmacol 31:61–72. 10.1097/FBP.0000000000000497 PubMed DOI

Cavaletti G, Cavalletti E, Oggioni N, Sottani C, Minoia C, D'Incalci M, Zucchetti M, Marmiroli P, Tredici G (2000) Distribution of paclitaxel within the nervous system of the rat after repeated intravenous administration. Neurotoxicology 21:389–393. PubMed

Chen SR, Zhu L, Chen H, Wen L, Laumet G, Pan HL (2014) Increased spinal cord Na(+)-K(+)-2Cl(-) cotransporter-1 (NKCC1) activity contributes to impairment of synaptic inhibition in paclitaxel-induced neuropathic pain. J Biol Chem 289:31111–31120. 10.1074/jbc.M114.600320 PubMed DOI PMC

Chiba T, Oka Y, Kambe T, Koizumi N, Abe K, Kawakami K, Utsunomiya I, Taguchi K (2016) Paclitaxel-induced peripheral neuropathy increases substance P release in rat spinal cord. Eur J Pharmacol 770:46–51. 10.1016/j.ejphar.2015.11.055 PubMed DOI

Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021. 10.1038/nature04223 PubMed DOI

Cunha TM, Roman-Campos D, Lotufo CM, Duarte HL, Souza GR, Verri WA, Funez MI, Dias QM, Schivo IR, Domingues AC, Sachs D, Chiavegatto S, Teixeira MM, Hothersall JS, Cruz JS, Cunha FQ, Ferreira SH (2010) Morphine peripheral analgesia depends on activation of the PI3K gamma/AKT/nNOS/NO/K-ATP signaling pathway. Proc Natl Acad Sci USA 107:4442–4447. 10.1073/pnas.0914733107 PubMed DOI PMC

Damoiseaux J, Dopp EA, Calame W, Chao D, Macpherson GG, Dijkstra CD (1994) Rat macrophage lysosomal membrane antigen recognized by monoclonal-antibody ED1. Immunology 83:140–147. PubMed PMC

Dittert I, Benedikt J, Vyklicky L, Zimmermann K, Reeh PW, Vlachova V (2006) Improved superfusion technique for rapid cooling or heating of cultured cells under patch-clamp conditions. J Neurosci Methods 151:178–185. 10.1016/j.jneumeth.2005.07.005 PubMed DOI

Drew GM, Lau BK, Vaughan CW (2009) Substance P drives endocannabinoid-mediated disinhibition in a midbrain descending analgesic pathway. J Neurosci 29:7220–7229. 10.1523/JNEUROSCI.4362-08.2009 PubMed DOI PMC

Duan B, Liu DS, Huang Y, Zeng WZ, Wang X, Yu H, Zhu MX, Chen ZY, Xu TL (2012) PI3-kinase/Akt pathway-regulated membrane insertion of acid-sensing ion channel 1a underlies BDNF-induced pain hypersensitivity. J Neurosci 32:6351–6363. 10.1523/JNEUROSCI.4479-11.2012 PubMed DOI PMC

Fang D, Kong LY, Cai J, Li S, Liu XD, Han JS, Xing GG (2015) Interleukin-6-mediated functional upregulation of TRPV1 receptors in dorsal root ganglion neurons through the activation of JAK/PI3K signaling pathway: roles in the development of bone cancer pain in a rat model. Pain 156:1124–1144. 10.1097/j.pain.0000000000000158 PubMed DOI

FDA (2018a) New drug application (NDA 211155). Multi-disciplinary review and evaluation: 5. Nonclinical pharmacology/toxicology, 5.3. ADME/PK, pp 37–40. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211155Orig1Orig2s000MultidisciplineR.pdf. Accessed Apr 15, 2021.

FDA (2018b) Duvelisib (COPIKTRA, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Available at https://www.fda.gov/drugs/resources-information-approved-drugs/duvelisib-copiktra-verastem-inc-adult-patients-elapsed-or-refractory-chronic-lymphocytic-leukemia. Accessed Apr 15, 2021.

FDA (2018c) New drug application (NDA 211155). Multi-disciplinary review and evaluation: 5. Nonclinical pharmacology/toxicology, 5.2. Pharmacology, pp 32–35. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211155Orig1Orig2s000MultidisciplineR.pdf. Accessed Apr 15, 2021.

Flinn IW, O'Brien S, Kahl B, Patel M, Oki Y, Foss FF, Porcu P, Jones J, Burger JA, Jain N, Kelly VM, Allen K, Douglas M, Sweeney J, Kelly P, Horwitz S (2018) Duvelisib, a novel oral dual inhibitor of PI3K-delta, gamma, is clinically active in advanced hematologic malignancies. Blood 131:877–887. 10.1182/blood-2017-05-786566 PubMed DOI PMC

Foster E, Wildner H, Tudeau L, Haueter S, Ralvenius WT, Jegen M, Johannssen H, Hosli L, Haenraets K, Ghanem A, Conzelmann KK, Bosl M, Zeilhofer HU (2015) Targeted ablation, silencing, and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch. Neuron 85:1289–1304. 10.1016/j.neuron.2015.02.028 PubMed DOI PMC

Guan Z, Kuhn JA, Wang X, Colquitt B, Solorzano C, Vaman S, Guan AK, Evans-Reinsch Z, Braz J, Devor M, Abboud-Werner SL, Lanier LL, Lomvardas S, Basbaum AI (2016) Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat Neurosci 19:94–101. 10.1038/nn.4189 PubMed DOI PMC

Horwitz SM, Koch R, Porcu P, Oki Y, Moskowitz A, Perez M, Myskowski P, Officer A, Jaffe JD, Morrow SN, Allen K, Douglas M, Stern H, Sweeney J, Kelly P, Kelly V, Aster JC, Weaver D, Foss FM, Weinstock DM (2018) Activity of the PI3K-delta,gamma inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood 131:888–898. 10.1182/blood-2017-08-802470 PubMed DOI PMC

Huang JX, Chen DT, Yan F, Wu SY, Kang SY, Xing W, Zeng WA, Xie JD (2020) JTC-801 alleviates mechanical allodynia in paclitaxel-induced neuropathic pain through the PI3K/Akt pathway. Eur J Pharmacol 883:1–7. PubMed

Huang ZZ, Li D, Liu CC, Cui Y, Zhu HQ, Zhang WW, Li YY, Xin WJ (2014) CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy. Brain Behav Immun 40:155–165. 10.1016/j.bbi.2014.03.014 PubMed DOI

Hwang BY, Kim ES, Kim CH, Kwon JY, Kim HK (2012) Gender differences in paclitaxel-induced neuropathic pain behavior and analgesic response in rats. Korean J Anesthesiol 62:66–72. 10.4097/kjae.2012.62.1.66 PubMed DOI PMC

Imlach WL, Bhola RF, Mohammadi SA, Christie MJ (2016) Glycinergic dysfunction in a subpopulation of dorsal horn interneurons in a rat model of neuropathic pain. Sci Rep 6:14. 10.1038/srep37104 PubMed DOI PMC

Jennings EA, Vaughan CW, Christie MJ (2001) Cannabinoid actions on rat superficial medullary dorsal horn neurons in vitro. J Physiol 534:805–812. 10.1111/j.1469-7793.2001.00805.x PubMed DOI PMC

Ji RR, Chamessian A, Zhang YQ (2016) Pain regulation by non-neuronal cells and inflammation. Science 354:572–577. 10.1126/science.aaf8924 PubMed DOI PMC

Kalynovska N, Diallo M, Sotakova-Kasparova D, Palecek J (2020) Losartan attenuates neuroinflammation and neuropathic pain in paclitaxel-induced peripheral neuropathy. J Cell Mol Med 24:7949–7958. 10.1111/jcmm.15427 PubMed DOI PMC

König C, Gavrilova-Ruch O, von Banchet GS, Bauer R, Grün M, Hirsch E, Rubio I, Schulz S, Heinemann SH, Schaible HG, Wetzker R (2010) Modulation of mu opioid receptor desensitization in peripheral sensory neurons by phosphoinositide 3-kinase gamma. Neuroscience 169:449–454. 10.1016/j.neuroscience.2010.04.068 PubMed DOI

Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10:895–926. 10.1016/j.jpain.2009.06.012 PubMed DOI PMC

Leinders M, Koehrn FJ, Bartok B, Boyle DL, Shubayev V, Kalcheva I, Yu NK, Park J, Kaang BK, Hefferan MP, Firestein GS, Sorkin LS (2014) Differential distribution of PI3K isoforms in spinal cord and dorsal root ganglia: potential roles in acute inflammatory pain. Pain 155:1150–1160. 10.1016/j.pain.2014.03.003 PubMed DOI PMC

Li Y, Zhang HJ, Zhang HM, Kosturakis AK, Jawad AB, Dougherty PM (2014) Toll-like receptor 4 signaling contributes to paclitaxel-induced peripheral neuropathy. J Pain 15:712–725. 10.1016/j.jpain.2014.04.001 PubMed DOI PMC

Li Y, Adamek P, Zhang H, Tatsui CE, Rhines LD, Mrozkova P, Li Q, Kosturakis AK, Cassidy RM, Harrison DS, Cata JP, Sapire K, Zhang H, Kennamer-Chapman RM, Jawad AB, Ghetti A, Yan J, Palecek J, Dougherty PM (2015) The cancer chemotherapeutic paclitaxel increases human and rodent sensory neuron responses to TRPV1 by activation of TLR4. J Neurosci 35:13487–13500. 10.1523/JNEUROSCI.1956-15.2015 PubMed DOI PMC

Li Y, Tatsui CE, Rhines LD, North RY, Harrison DS, Cassidy RM, Johansson CA, Kosturakis AK, Edwards DD, Zhang H, Dougherty PM (2017) Dorsal root ganglion neurons become hyperexcitable and increase expression of voltage-gated T-type calcium channels (Cav3.2) in paclitaxel-induced peripheral neuropathy. Pain 158:417–429. 10.1097/j.pain.0000000000000774 PubMed DOI PMC

Liu CC, Lu N, Cui Y, Yang T, Zhao ZQ, Xin WJ, Liu XG (2010) Prevention of paclitaxel-induced allodynia by minocycline: effect on loss of peripheral nerve fibers and infiltration of macrophages in rats. Mol Pain 6:76–78. 10.1186/1744-8069-6-76 PubMed DOI PMC

Liu W, Lv Y, Ren F (2018) PI3K/Akt pathway is required for spinal central sensitization in neuropathic pain. Cell Mol Neurobiol 38:747–755. 10.1007/s10571-017-0541-x PubMed DOI

Lu Y, Dong H, Gao Y, Gong Y, Ren Y, Gu N, Zhou S, Xia N, Sun Y-Y, Ji R-R, Xiong L (2013) A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia. J Clin Invest 123:4050–4062. 10.1172/JCI70026 PubMed DOI PMC

Malin SA, Davis BM, Molliver DC (2007) Production of dissociated sensory neuron cultures and considerations for their use in studying neuronal function and plasticity. Nat Protoc 2:152–160. 10.1038/nprot.2006.461 PubMed DOI

Malyshev I, Malyshev Y (2015) Current concept and update of the macrophage plasticity concept: intracellular mechanisms of reprogramming and m3 macrophage 'switch' phenotype. Biomed Res Int 2015:341308. 10.1155/2015/341308 PubMed DOI PMC

Manjavachi MN, Passos GF, Trevisan G, Araujo SB, Pontes JP, Fernandes ES, Costa R, Calixto JB (2019) Spinal blockage of CXCL1 and its receptor CXCR2 inhibits paclitaxel-induced peripheral neuropathy in mice. Neuropharmacology 151:136–143. 10.1016/j.neuropharm.2019.04.014 PubMed DOI

Mapplebeck JC, Beggs S, Salter MW (2016) Sex differences in pain: a tale of two immune cells. Pain 157:S2–S6. 10.1097/j.pain.0000000000000389 PubMed DOI

Masocha W, Parvathy SS (2016) Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain. PeerJ 4:e2798. 10.7717/peerj.2798 PubMed DOI PMC

Meesawatsom P, Hathway G, Bennett A, Constantin-Teodosiu D, Chapman V (2020) Spinal neuronal excitability and neuroinflammation in a model of chemotherapeutic neuropathic pain: targeting the resolution pathways. J Neuroinflamm 17:17. PubMed PMC

Mogil JS (2012) Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon. Nat Rev Neurosci 13:859–866. 10.1038/nrn3360 PubMed DOI

Mouchemore KA, Sampaio NG, Murrey MW, Stanley ER, Lannutti BJ, Pixley FJ (2013) Specific inhibition of PI3K p110 delta inhibits CSF-1-induced macrophage spreading and invasive capacity. FEBS J 280:5228–5236. 10.1111/febs.12316 PubMed DOI PMC

Muller F, Heinke B, Sandkuhler J (2003) Reduction of glycine receptor-mediated miniature inhibitory postsynaptic currents in rat spinal lamina I neurons after peripheral inflammation. Neuroscience 122:799–805. 10.1016/j.neuroscience.2003.07.009 PubMed DOI

Paller CJ, Campbell CM, Edwards RR, Dobs AS (2009) Sex-based differences in pain perception and treatment. Pain Med 10:289–299. 10.1111/j.1526-4637.2008.00558.x PubMed DOI PMC

Park SB, Goldstein D, Krishnan AV, Lin CS, Friedlander ML, Cassidy J, Koltzenburg M, Kiernan MC (2013) Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin 63:419–437. 10.3322/caac.21204 PubMed DOI

Peng JY, Gu N, Zhou LJ, Eyo UB, Murugan M, Gan WB, Wu LJ (2016) Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury. Nat Commun 7:12029. 10.1038/ncomms12029 PubMed DOI PMC

Pernia-Andrade AJ, Kato A, Witschi R, Nyilas R, Katona I, Freund TF, Watanabe M, Filitz J, Koppert W, Schuttler J, Ji G, Neugebauer V, Marsicano G, Lutz B, Vanegas H, Zeilhofer HU (2009) Spinal endocannabinoids and CB1 receptors mediate C-fiber-induced heterosynaptic pain sensitization. Science 325:760–764. 10.1126/science.1171870 PubMed DOI PMC

Peters CM, Jimenez-Andrade JM, Jonas BM, Sevcik MA, Koewler NJ, Ghilardi JR, Wong GY, Mantyh PW (2007) Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells. Exp Neurol 203:42–54. 10.1016/j.expneurol.2006.07.022 PubMed DOI

Pezet S, Marchand F, D'Mello R, Grist J, Clark AK, Malcangio M, Dickenson AH, Williams RJ, McMahon SB (2008) Phosphatidylinositol 3-kinase is a key mediator of central sensitization in painful inflammatory conditions. J Neurosci 28:4261–4270. 10.1523/JNEUROSCI.5392-07.2008 PubMed DOI PMC

Reyes-Gibby CC, Morrow PK, Buzdar A, Shete S (2009) Chemotherapy-induced peripheral neuropathy as a predictor of neuropathic pain in breast cancer patients previously treated with paclitaxel. J Pain 10:1146–1150. 10.1016/j.jpain.2009.04.006 PubMed DOI PMC

Sandkühler J (2009) Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 89:707–758. 10.1152/physrev.00025.2008 PubMed DOI

Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, Colvin LA, Fallon M (2014) Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Pain 155:2461–2470. 10.1016/j.pain.2014.09.020 PubMed DOI

Sharif O, Brunner JS, Vogel A, Schabbauer G (2019) Macrophage rewiring by nutrient associated PI3K dependent pathways. Front Immunol 10:2002. PubMed PMC

Sisignano M, Angioni C, Park CK, Meyer Dos Santos S, Jordan H, Kuzikov M, Liu D, Zinn S, Hohman SW, Schreiber Y, Zimmer B, Schmidt M, Lu R, Suo J, Zhang DD, Schäfer SM, Hofmann M, Yekkirala AS, de Bruin N, Parnham MJ, et al. . (2016) Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain. Proc Natl Acad Sci USA 113:12544–12549. 10.1073/pnas.1613246113 PubMed DOI PMC

Sivilotti L, Woolf CJ (1994) The contribution of GABAA and glycine receptors to central sensitization: disinhibition and touch-evoked allodynia in the spinal cord. J Neurophysiol 72:169–179. 10.1152/jn.1994.72.1.169 PubMed DOI

Spicarova D, Nerandzic V, Palecek J (2011) Modulation of spinal cord synaptic activity by tumor necrosis factor alpha in a model of peripheral neuropathy. J Neuroinflamm 8:177. PubMed PMC

Spicarova D, Nerandzic V, Palecek J (2014a) Update on the role of spinal cord TRPV1 receptors in pain modulation. Physiol Res 63:S225–S236. 10.33549/physiolres.932713 PubMed DOI

Spicarova D, Adamek P, Kalynovska N, Mrozkova P, Palecek J (2014b) TRPV1 receptor inhibition decreases CCL2-induced hyperalgesia. Neuropharmacology 81:75–84. 10.1016/j.neuropharm.2014.01.041 PubMed DOI

Stein AT, Ufret-Vincenty CA, Hua L, Santana LF, Gordon SE (2006) Phosphoinositide 3-kinase binds to TRPV1 and mediates NGF-stimulated TRPV1 trafficking to the plasma membrane. J Gen Physiol 128:509–522. 10.1085/jgp.200609576 PubMed DOI PMC

Stratiievska A, Nelson S, Senning EN, Lautz JD, Smith SE, Gordon SE (2018) Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor. eLife 7:17. 10.7554/eLife.38869 PubMed DOI PMC

Svobodova I, Bhattaracharya A, Ivetic M, Bendova Z, Zemkova H (2018) Circadian ATP release in organotypic cultures of the rat suprachiasmatic nucleus is dependent on P2X7 and P2Y receptors. Front Pharmacol 9:192. PubMed PMC

Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 11:329–341. 10.1038/nrm2882 PubMed DOI

Verastem (2018) Copiktra (duvelisib), capsules for oral use: US prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211155s000lbl.pdf. Accessed May 4, 2021.

Viard P, Butcher AJ, Halet G, Davies A, Nurnberg B, Heblich F, Dolphin AC (2004) PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane. Nat Neurosci 7:939–946. 10.1038/nn1300 PubMed DOI

Wanderley CW, Colon DF, Luiz JP, Oliveira FF, Viacava PR, Leite CA, Pereira JA, Silva CM, Silva CR, Silva RL, Speck-Hernandez CA, Mota JM, Alves JC, Lima RC, Cunha TM, Cunha FQ (2018) Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1 profile in a TLR4-dependent manner. Cancer Res 78:5891–5900. 10.1158/0008-5472.CAN-17-3480 PubMed DOI

Wigerblad G, Huie JR, Yin HZ, Leinders M, Pritchard RA, Koehrn FJ, Xiao WH, Bennett GJ, Huganir RL, Ferguson AR, Weiss JH, Svensson CI, Sorkin LS (2017) Inflammation-induced GluA1 trafficking and membrane insertion of Ca2+ permeable AMPA receptors in dorsal horn neurons is dependent on spinal tumor necrosis factor, PI3 kinase and protein kinase A. Exp Neurol 293:144–158. 10.1016/j.expneurol.2017.04.004 PubMed DOI PMC

Winkler DG, Faia KL, DiNitto JP, Ali JA, White KF, Brophy EE, Pink MM, Proctor JL, Lussier J, Martin CM, Hoyt JG, Tillotson B, Murphy EL, Lim AR, Thomas BD, Macdougall JR, Ren P, Liu Y, Li LS, Jessen KA, et al. . (2013) PI3K-delta and PI3K-gamma Inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol 20:1364–1374. 10.1016/j.chembiol.2013.09.017 PubMed DOI

Wu J, Hocevar M, Bie B, Foss JF, Naguib M (2019) Cannabinoid type 2 receptor system modulates paclitaxel-induced microglial dysregulation and central sensitization in rats. J Pain 20:501–514. 10.1016/j.jpain.2018.10.007 PubMed DOI

Xu B, Mo C, Lv CM, Liu SS, Li J, Chen JY, Wei YH, An HW, Ma L, Guan XH (2019) Post-surgical inhibition of phosphatidylinositol 3-kinase attenuates the plantar incision-induced postoperative pain behavior via spinal Akt activation in male mice. BMC Neurosci 20:10. 10.1186/s12868-019-0521-9 PubMed DOI PMC

Xu JT, Tu HY, Xin WJ, Liu XG, Zhang GH, Zhai CH (2007) Activation of phosphatidylinositol 3-kinase and protein kinase B/Akt in dorsal root ganglia and spinal cord contributes to the neuropathic pain induced by spinal nerve ligation in rats. Exp Neurol 206:269–279. 10.1016/j.expneurol.2007.05.029 PubMed DOI

Yadav R, Yan XS, Maixner DW, Gao M, Weng HR (2015) Blocking the GABA transporter GAT-1 ameliorates spinal GABAergic disinhibition and neuropathic pain induced by paclitaxel. J Neurochem 133:857–869. 10.1111/jnc.13103 PubMed DOI PMC

Yan X, Jiang E, Weng HR (2015a) Activation of toll like receptor 4 attenuates GABA synthesis and postsynaptic GABA receptor activities in the spinal dorsal horn via releasing interleukin-1 beta. J Neuroinflammation 12:222. 10.1186/s12974-014-0222-3 PubMed DOI PMC

Yan X, Maixner DW, Yadav R, Gao M, Li P, Bartlett MG, Weng HR (2015b) Paclitaxel induces acute pain via directly activating toll like receptor 4. Mol Pain 11:10. 10.1186/s12990-015-0005-6 PubMed DOI PMC

Yan X, Li F, Maixner DW, Yadav R, Gao M, Ali MW, Hooks SB, Weng HR (2019) Interleukin-1beta released by microglia initiates the enhanced glutamatergic activity in the spinal dorsal horn during paclitaxel-associated acute pain syndrome. Glia 67:482–497. 10.1002/glia.23557 PubMed DOI

Yu XB, Liu HJ, Hamel KA, Morvan MG, Yu S, Leff J, Guan ZH, Braz JM, Basbaum AI (2020) Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain. Nat Commun 11:12. 10.1038/s41467-019-13839-2 PubMed DOI PMC

Zeilhofer HU (2008) Loss of glycinergic and GABAergic inhibition in chronic pain: contributions of inflammation and microglia. Int Immunopharmacol 8:182–187. 10.1016/j.intimp.2007.07.009 PubMed DOI

Zeilhofer HU, Wildner H, Yevenes GE (2012) Fast synaptic inhibition in spinal sensory processing and pain control. Physiol Rev 92:193–235. 10.1152/physrev.00043.2010 PubMed DOI PMC

Zhang H, Yoon SY, Zhang H, Dougherty PM (2012) Evidence that spinal astrocytes but not microglia contribute to the pathogenesis of paclitaxel-induced painful neuropathy. J Pain 13:293–303. 10.1016/j.jpain.2011.12.002 PubMed DOI PMC

Zhang H, Boyette-Davis JA, Kosturakis AK, Li Y, Yoon SY, Walters ET, Dougherty PM (2013) Induction of monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 in primary sensory neurons contributes to paclitaxel-induced peripheral neuropathy. J Pain 14:1031–1044. 10.1016/j.jpain.2013.03.012 PubMed DOI PMC

Zhang H, Li Y, de Carvalho-Barbosa M, Kavelaars A, Heijnen CJ, Albrecht PJ, Dougherty PM (2016) Dorsal root ganglion infiltration by macrophages contributes to paclitaxel chemotherapy-induced peripheral neuropathy. J Pain 17:775–786. 10.1016/j.jpain.2016.02.011 PubMed DOI PMC

Zhang J, Wang LP, Wang HS, Su ZB, Pang XC (2019) Neuroinflammation and central PI3K/Akt/mTOR signal pathway contribute to bone cancer pain. Mol Pain 15:1744806919830240. 10.1177/1744806919830240 PubMed DOI PMC

Zhang MY, Jin FH, Zhu YC, Qi F (2020) Peripheral FGFR1 regulates myofascial pain in rats via the PI3K/AKT pathway. Neuroscience 436:1–10. 10.1016/j.neuroscience.2020.04.002 PubMed DOI

Zhang XM, Huang JH, McNaughton PA (2005) NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J 24:4211–4223. 10.1038/sj.emboj.7600893 PubMed DOI PMC

Zhao S, Ting JT, Atallah HE, Qiu L, Tan J, Gloss B, Augustine GJ, Deisseroth K, Luo M, Graybiel AM, Feng G (2011) Cell type-specific channelrhodopsin-2 transgenic mice for optogenetic dissection of neural circuitry function. Nat Methods 8:745–752. 10.1038/nmeth.1668 PubMed DOI PMC

Zhu WG, Oxford GS (2007) Phosphoinositide-3-kinase and mitogen activated protein kinase signaling pathways mediate acute NGF sensitization of TRPV1. Mol Cell Neurosci 34:689–700. 10.1016/j.mcn.2007.01.005 PubMed DOI PMC

Zhuang ZY, Xu H, Clapham DE, Ji RR (2004) Phosphatidylinositol 3-kinase activates ERK in primary sensory neurons and mediates inflammatory heat hyperalgesia through TRPV1 sensitization. J Neurosci 24:8300–8309. 10.1523/JNEUROSCI.2893-04.2004 PubMed DOI PMC