title: Aromatase inhibitors augment nociceptive behaviors in rats and enhance the excitability of sensory neurons.
abstract: Although aromatase inhibitors (AIs) are commonly used therapies for breast cancer, their use is limited because they produce arthralgia in a large number of patients. To determine whether AIs produce hypersensitivity in animal models of pain, we examined the effects of the AI, letrozole, on mechanical, thermal, and chemical sensitivity in rats. In ovariectomized (OVX) rats, administering a single dose of 1 or 5mg/kg letrozole significantly reduced mechanical paw withdrawal thresholds, without altering thermal sensitivity. Repeated injection of 5mg/kg letrozole in male rats produced mechanical, but not thermal, hypersensitivity that extinguished when drug dosing was stopped. A single dose of 5mg/kg letrozole or daily dosing of letrozole or exemestane in male rats also augmented flinching behavior induced by intraplantar injection of 1000nmol of adenosine 5'-triphosphate (ATP). To determine whether sensitization of sensory neurons contributed to AI-induced hypersensitivity, we evaluated the excitability of neurons isolated from dorsal root ganglia of male rats chronically treated with letrozole. Both small and medium-diameter sensory neurons isolated from letrozole-treated rats were more excitable, as reflected by increased action potential firing in response to a ramp of depolarizing current, a lower resting membrane potential, and a lower rheobase. However, systemic letrozole treatment did not augment the stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP) from spinal cord slices, suggesting that the enhanced nociceptive responses were not secondary to an increase in peptide release from sensory endings in the spinal cord. These results provide the first evidence that AIs modulate the excitability of sensory neurons, which may be a primary mechanism for the effect of these drugs to augment pain behaviors in rats.
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: jrobarge@iu.edu.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Robarge
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States; Laboratório de Farmacologia Molecular, Faculdade de Ciências da Saúde, Universidade de Brasília, Brazil. Electronic address: djane@unb.br.
authors.forename: Djane B
authors.initials: DB
authors.lastname: Duarte
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: bshariat@umail.iu.edu.
authors.forename: Behzad
authors.initials: B
authors.lastname: Shariati
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: rewang@iupui.edu.
authors.forename: Ruizhong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: dflockha@iupui.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: vaskom@iupui.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Vasko
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000730:Androstadienes / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000139:chemically induced*; D006987:Hypesthesia / Q000139:chemically induced; D000077289:Letrozole; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009570:Nitriles / Q000009:adverse effects / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects*; D010052:Ovariectomy; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014230:Triazoles / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D000255:Adenosine Triphosphate; D015740:Calcitonin Gene-Related Peptide; C056516:exemestane
keywords: Aromatase inhibitors; Calcitonin gene-related peptide; Electrophysiology; Excitability; Exemestane; Hypersensitivity; Letrozole; Nociception; Pain; Sensory neuron