Principal Investigator

Jon David
Levine
Awardee Organization

University Of California, San Francisco
United States

Fiscal Year
2023
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Chronic Chemotherapy Peripheral Neuropathy: Role of Neuroplasticity and Stress

The premise of this research project is that nociceptor neuroplasticity is an important mechanism underlying chronic chemotherapy-induced peripheral neuropathy (CIPN) and that stress plays a key role in the induction of this neuroplasticity. In this grant, we will evaluate the role of nociceptor neuroplasticity in chronic CIPN induced by two clinically important classes of cancer chemotherapy (CTX), i.e., platinum and taxane compounds. Experiments will evaluate the role of diverse stressors (i.e., CTX administration, early life stress, adult chronic stress, prior to, during or after CTX), drugs used to treat co-morbid medical conditions that also act on stress axis mediator receptors (i.e., glucocorticoid and catecholamine), as well as resilience (i.e., resistance to stress) on the development of chronic CIPN. In addition, we will study neuroplasticity and stress in two other clinically important features of chronic CIPN that remain poorly understood: 1) platinum-induced cold allodynia and 2) “coasting” (i.e., worsening of CIPN after stopping CTX). Finally, we will harvest dorsal root ganglia (DRG), as well as blood, from rats exposed to CTX and stress to evaluate changes in gene expression in blood and the peripheral nervous system. These analyses will allow us to better identify risk factors for, and potential mechanisms of, chronic CIPN and could be used to help interpret future clinical studies to identify patients’ susceptibility for development of CIPN. The results of the proposed preclinical experiments have important clinical implications, including: 1) increased knowledge of the role of mechanisms of neuroplasticity underlying chronic CIPN that could identify new therapeutic targets to prevent and treat chronic CIPN; 2) increased understanding of how neuroendocrine stress axis mediators, acting at their cognate receptors on sensory neurons, contribute to chronic CIPN; 3) understanding mechanisms responsible for loss of efficacy of opioid analgesics in CIPN and its relationship to induction of nociceptor neuroplasticity; 4) understanding the mechanism of oxaliplatin-induced cold allodynia; 5) determining if tapering instead of stopping CTX mitigates coasting; and 6) elucidate genomic biomarkers for the development of chronic CIPN.

Publications

  • Xu Z, Lee MC, Sheehan K, Fujii K, Rabl K, Rader G, Varney S, Sharma M, Eilers H, Kober K, Miaskowski C, Levine JD, Schumacher MA. Chemotherapy for pain: reversing inflammatory and neuropathic pain with the anticancer agent mithramycin A. Pain. 2024 Jan 1;165(1):54-74. Epub 2023 Jun 27. PMID: 37366593
  • Staurengo-Ferrari L, Araldi D, Green PG, Levine JD. Neuroendocrine mechanisms in oxaliplatin-induced hyperalgesic priming. Pain. 2023 Jun 1;164(6):1375-1387. Epub 2022 Dec 6. PMID: 36729863
  • Bonet IJM, Staurengo-Ferrari L, Araldi D, Green PG, Levine JD. Second messengers mediating high-molecular-weight hyaluronan-induced antihyperalgesia in rats with chemotherapy-induced peripheral neuropathy. Pain. 2022 Sep 1;163(9):1728-1739. Epub 2021 Dec 6. PMID: 34913881
  • Schumacher MA. Peripheral Neuroinflammation and Pain: How Acute Pain Becomes Chronic. Current neuropharmacology. 2024;22(1):6-14. PMID: 37559537
  • Ferrari LF, Araldi D, Green PG, Levine JD. Marked sexual dimorphism in neuroendocrine mechanisms for the exacerbation of paclitaxel-induced painful peripheral neuropathy by stress. Pain. 2020 Apr;161(4):865-874. PMID: 31917777
  • Mansooralavi N, Khomula EV, Levine JD. Duloxetine prevents bortezomib and paclitaxel large-fiber chemotherapy-induced peripheral neuropathy (LF-CIPN) in sprague dawley rats. Molecular pain. 2023 Jan-Dec;19:17448069231185694. PMID: 37338165
  • Staurengo-Ferrari L, Bonet IJM, Araldi D, Green PG, Levine JD. Neuroendocrine Stress Axis-Dependence of Duloxetine Analgesia (Anti-Hyperalgesia) in Chemotherapy-Induced Peripheral Neuropathy. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2022 Jan 19;42(3):405-415. Epub 2021 Dec 8. PMID: 34880120
  • Staurengo-Ferrari L, Green PG, Araldi D, Ferrari LF, Miaskowski C, Levine JD. Sexual dimorphism in the contribution of neuroendocrine stress axes to oxaliplatin-induced painful peripheral neuropathy. Pain. 2021 Mar 1;162(3):907-918. PMID: 32947545
  • Bonet IJM, Araldi D, Bogen O, Levine JD. Involvement of TACAN, a Mechanotransducing Ion Channel, in Inflammatory But Not Neuropathic Hyperalgesia in the Rat. The journal of pain. 2021 May;22(5):498-508. Epub 2020 Nov 21. PMID: 33232830
  • Bonet IJM, Araldi D, Green PG, Levine JD. Topical coapplication of hyaluronan with transdermal drug delivery enhancers attenuates inflammatory and neuropathic pain. Pain. 2023 Dec 1;164(12):2653-2664. Epub 2023 Jul 18. PMID: 37467181
  • Khomula EV, Araldi D, Green PG, Levine JD. Sensitization of human and rat nociceptors by low dose morphine is toll-like receptor 4-dependent. Molecular pain. 2024 Jan-Dec;20:17448069241227922. PMID: 38195088
  • Bogen O, Araldi D, Sucher A, Kober K, Ohara PT, Levine JD. Isolectin B4 (IB4)-conjugated streptavidin for the selective knockdown of proteins in IB4-positive (+) nociceptors. Molecular pain. 2024 Jan-Dec;20:17448069241230419. PMID: 38246917