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1.
Pharmacol Res ; 90: 67-75, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25304184

ABSTRACT

Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [(3)H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [(3)H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model.


Subject(s)
Analgesics/therapeutic use , Benzodioxoles/therapeutic use , Hyperalgesia/drug therapy , Neuralgia/drug therapy , Piperidines/therapeutic use , Amides , Analgesics/pharmacology , Animals , Antineoplastic Agents , Arachidonic Acids/metabolism , Arachidonic Acids/pharmacology , Benzodioxoles/pharmacology , Cells, Cultured , Cisplatin , Disease Models, Animal , Endocannabinoids/metabolism , Endocannabinoids/pharmacology , Ethanolamines/metabolism , Ganglia, Spinal/cytology , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Glycerides/metabolism , Glycerides/pharmacology , Hyperalgesia/metabolism , Indoles/pharmacology , Male , Mesencephalon/drug effects , Mesencephalon/metabolism , Mice , Mice, Inbred C3H , Monoacylglycerol Lipases/antagonists & inhibitors , Morpholines/pharmacology , Neuralgia/chemically induced , Neuralgia/metabolism , Palmitic Acids/metabolism , Piperidines/pharmacology , Polyunsaturated Alkamides/metabolism , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Receptor, Cannabinoid, CB2/metabolism , Skin/drug effects , Skin/metabolism , Spinal Cord/drug effects , Spinal Cord/metabolism
2.
Neurotoxicology ; 39: 124-31, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24035926

ABSTRACT

Bortezomib is part of a newer class of chemotherapeutic agents whose mechanism of action is inhibition of the proteasome-ubiquitination system. Primarily used in multiple myeloma, bortezomib causes a sensory-predominant axonal peripheral neuropathy in approximately 30% of patients. There are no established useful preventative agents for bortezomib-induced peripheral neuropathy (BIPN), and the molecular mechanisms of BIPN are unknown. We have developed an in vitro model of BIPN using rat dorsal root ganglia neuronal cultures. At clinically-relevant dosages, bortezomib produces a sensory axonopathy as evidenced by whole explant outgrowth and cell survival assays. This sensory axonopathy is associated with alterations in tubulin and results in accumulation of somatic tubulin without changes in microtubule ultrastructure. Furthermore, we observed an increased proportion of polymerized tubulin, but not total or acetylated tubulin, in bortezomib-treated DRG neurons. Similar findings are observed with lactacystin, an unrelated proteasome-inhibitor, which argues for a class effect of proteasome inhibition on dorsal root ganglion neurons. Finally, there is a change in axonal transport of mitochondria induced by bortezomib in a time-dependent fashion. In summary, we have developed an in vitro model of BIPN that recapitulates the clinical sensory axonopathy; this model demonstrates that bortezomib induces an alteration in microtubules and axonal transport. This robust model will be used in future mechanistic studies of BIPN and its prevention.


Subject(s)
Antineoplastic Agents/pharmacology , Axonal Transport/drug effects , Boronic Acids/pharmacology , Ganglia, Spinal/cytology , Microtubules/metabolism , Neurons/drug effects , Pyrazines/pharmacology , Acetylcysteine/analogs & derivatives , Acetylcysteine/pharmacology , Animals , Bortezomib , Cell Death/drug effects , Cells, Cultured , Cysteine Proteinase Inhibitors/pharmacology , Dose-Response Relationship, Drug , Embryo, Mammalian , Microscopy, Electron, Transmission , Microtubules/ultrastructure , Neurons/ultrastructure , Organ Culture Techniques , Rats , Rats, Sprague-Dawley , Statistics, Nonparametric , Time Factors
3.
J Neurosci ; 32(20): 7091-101, 2012 May 16.
Article in English | MEDLINE | ID: mdl-22593077

ABSTRACT

Painful peripheral neuropathy is a dose-limiting complication of chemotherapy. Cisplatin produces a cumulative toxic effect on peripheral nerves, and 30-40% of cancer patients receiving this agent experience pain. By modeling cisplatin-induced hyperalgesia in mice with daily injections of cisplatin (1 mg/kg, i.p.) for 7 d, we investigated the anti-hyperalgesic effects of anandamide (AEA) and cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597), an inhibitor of AEA hydrolysis. Cisplatin-induced mechanical and heat hyperalgesia were accompanied by a decrease in the level of AEA in plantar paw skin. No changes in motor activity were observed after seven injections of cisplatin. Intraplantar injection of AEA (10 µg/10 µl) or URB597 (9 µg/10 µl) transiently attenuated hyperalgesia through activation of peripheral CB1 receptors. Co-injections of URB597 (0.3 mg/kg daily, i.p.) with cisplatin decreased and delayed the development of mechanical and heat hyperalgesia. The effect of URB597 was mediated by CB1 receptors since AM281 (0.33 mg/kg daily, i.p.) blocked the effect of URB597. Co-injection of URB597 also normalized the cisplatin-induced decrease in conduction velocity of Aα/Aß-fibers and reduced the increase of ATF-3 and TRPV1 immunoreactivity in dorsal root ganglion (DRG) neurons. Since DRGs are a primary site of toxicity by cisplatin, effects of cisplatin were studied on cultured DRG neurons. Incubation of DRG neurons with cisplatin (4 µg/ml) for 24 h decreased the total length of neurites. URB597 (100 nM) attenuated these changes through activation of CB1 receptors. Collectively, these results suggest that pharmacological facilitation of AEA signaling is a promising strategy for attenuating cisplatin-associated sensory neuropathy.


Subject(s)
Arachidonic Acids/therapeutic use , Benzamides/therapeutic use , Carbamates/therapeutic use , Cisplatin/antagonists & inhibitors , Hyperalgesia/drug therapy , Neurotoxicity Syndromes/drug therapy , Peripheral Nervous System Diseases/drug therapy , Polyunsaturated Alkamides/therapeutic use , Receptor, Cannabinoid, CB1/agonists , Activating Transcription Factor 3/metabolism , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/antagonists & inhibitors , Arachidonic Acids/pharmacokinetics , Arachidonic Acids/pharmacology , Benzamides/antagonists & inhibitors , Benzamides/pharmacology , Cannabinoid Receptor Modulators/pharmacokinetics , Cannabinoid Receptor Modulators/pharmacology , Cannabinoid Receptor Modulators/therapeutic use , Carbamates/antagonists & inhibitors , Carbamates/pharmacology , Cells, Cultured , Cisplatin/adverse effects , Disease Models, Animal , Drug Interactions , Endocannabinoids , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Hyperalgesia/chemically induced , Male , Mice , Mice, Inbred C3H , Morpholines/pharmacology , Motor Activity/drug effects , Neurites/drug effects , Peripheral Nervous System Diseases/chemically induced , Polyunsaturated Alkamides/pharmacokinetics , Polyunsaturated Alkamides/pharmacology , Pyrazoles/pharmacology , TRPV Cation Channels/metabolism
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