title: Prophylactic treatment with the tricyclic antidepressant desipramine prevents development of paclitaxel-induced neuropathic pain through activation of endogenous analgesic systems.
abstract: Neuropathic pain impacts approximately 3-4.5% of the global population and remains an unresolved health problem. The management of neuropathic pain has two distinct goals-prevention of development and control of established neuropathic pain. We examined the impact of both prophylactic and therapeutic treatments with the tricyclic antidepressant desipramine on the development and maintenance of toxic neuropathic pain induced by the chemotherapeutic agent paclitaxel. We also investigated the involvement of endogenous analgesic (i.e., endogenous opioid and endocannabinoid) systems in the antinociceptive actions of desipramine in these two distinct phases of neuropathic pain. Chronic subcutaneous infusion of desipramine via osmotic pumps suppressed both the development and maintenance of paclitaxel-induced neuropathic pain. However, only prophylactic desipramine treatment blocked the development of neuropathic pain throughout the three month observation interval; neuropathic pain did not return. The opioid receptor antagonist naloxone blocked the antinociceptive effects of both prophylactic and therapeutic desipramine treatments throughout the entire timecourse of desipramine-induced antinociception. By contrast, cannabinoid CB1and CB2receptor antagonists partially attenuated the antinociceptive actions of desipramine in a manner that was restricted to the development phase of paclitaxel-induced neuropathic pain only. Paclitaxel decreased cell viability in TMD231 tumor cells in an MTT assay in vitro. Notably, desipramine (1nM-1μM) alone did not alter tumor cell viability and did not prevent the cytotoxic effects of paclitaxel under identical conditions. The highest concentration of desipramine (10μM) reduced tumor cell viability alone and enhanced the cytotoxic effects of paclitaxel. Our study identifies a previously unrecognized preemptive analgesic strategy that prevents development of paclitaxel-induced neuropathic pain, and also dissects receptor mechanisms underlying desipramine-induced antinociceptive effects. This information may be applied to improve current therapeutic strategies with the goal of preventing and managing neuropathic pain induced by chemotherapeutic treatment.
authors: Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA; Interdisciplinary Biochemistry Graduate Program, Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, USA.
authors: Liting
authors: L
authors: Deng
authors: Interdisciplinary Biochemistry Graduate Program, Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, USA.
authors: Wan-Hung
authors: WH
authors: Lee
authors: Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA.
authors: Zhili
authors: Z
authors: Xu
authors: Center for Drug Discovery, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA.
authors: Alexandros
authors: A
authors: Makriyannis
authors: Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA; Interdisciplinary Biochemistry Graduate Program, Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, USA; Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA. Electronic address: hohmanna@indiana.edu.
authors: Andrea G
authors: AG
authors: Hohmann
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D003891:Desipramine / Q000494:pharmacology / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D009437:Neuralgia / Q000139:chemically induced* / Q000517:prevention & control*; D017239:Paclitaxel / Q000009:adverse effects*; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000929:Antidepressive Agents, Tricyclic; D000972:Antineoplastic Agents, Phytogenic; D043882:Receptors, Cannabinoid; D017239:Paclitaxel; D003891:Desipramine
keywords: Antidepressant; Chemotherapy; Neuropathic pain; Norepinephrine; Opioid; Tumor cell viability