Cold exposure and a variety of types of mild stress increase pain in patients with painful disorders such as fibromyalgia syndrome. Acutely, stress induces thermogenesis by increasing sympathetic activation of beta-3 (β3) adrenergic receptors in brown adipose tissue. Chronic stress leads to the hypertrophy of brown adipose, a phenomenon termed adaptive thermogenesis. Based on the innervation of skeletal muscle by collaterals of nerves projecting to brown adipose, we theorized an association between brown adipose tissue activity and musculoskeletal hyperalgesia and tested this hypothesis in mice. Exposure to a cold swim or injection of BRL37344 (β3 adrenergic agonist) each enhanced musculoskeletal hyperalgesia, as indicated by morphine-sensitive decreases in grip force responses, whereas SR59230A (β3 adrenergic antagonist) attenuated swim-induced hyperalgesia. Chemical ablation of interscapular brown adipose, using Rose Bengal, attenuated the development of hyperalgesia in response to either swim stress or BRL37344. In addition, elimination of the gene expressing uncoupling protein-1 (UCP1), the enzyme responsible for thermogenesis, prevented musculoskeletal hyperalgesia in response to either a swim or BRL37344, as documented in UCP1-knockout (UCP1-KO) mice compared with wild-type controls. Together, these data provide a convergence of evidence suggesting that activation of brown adipose contributes to stress-induced musculoskeletal hyperalgesia.
Musculoskeletal hyperalgesia, measured using the grip force assay in mice, can be induced by either a forced swim stress or activation of β3 adrenergic receptors and is attenuated by either prior ablation of brown adipose tissue or by elimination of UCP1 activity. Although brown adipose is typically associated with thermogenesis, brown adipose or its associated nerves may also support musculoskeletal hyperalgesia induced by stress.
Departments of aVeterinary and Biomedical Sciences and
bMedicinal Chemistry, University of Minnesota, Minneapolis, MN, USA
Corresponding author. Address: Department of Veterinary Biomedical Sciences, University of Minnesota, 1988 Fitch Ave, Rm 295, St. Paul, MN 55108, USA. Tel.: +1-612-624-3650; fax: +1-612-625-0204. E-mail address: firstname.lastname@example.org (A. A. Larson).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received April 19, 2016
Received in revised form July 12, 2016
Accepted July 14, 2016