Androgen receptor transcriptionally regulates μ-opioid receptor expression in rat trigeminal ganglia.
The involvement of testosterone in pain, inflammation, and analgesia has been reported, but the role of androgen receptor (AR), a steroid receptor for testosterone, is not well understood. We have previously shown that peripheral inflammation upregulates μ-opioid receptor (MOR) in rat trigeminal ganglia (TG) in a testosterone-dependent manner. In this study, we hypothesized that testosterone regulates MOR expression via transcriptional activities of AR in TG. We first examined whether AR is co-expressed with MOR in TG neurons. Our immunohistochemical experiment revealed that AR staining is detected in neurons of all sizes in TG and that a subset of AR is expressed in MOR as well as in TRPV1-positive neurons. We identified the promoter region of the rat MOR gene contains putative AR binding sites. Using chromatin immunoprecipitation assay, we demonstrated that AR directly binds to these sites in TG extracts. We confirmed with luciferase reporter assay that AR activated the MOR promoter in response to androgens in a human neuroblastoma cell line (5H-5YSY). These data demonstrated that AR functions as a transcriptional regulator of the MOR gene activity. Finally, we showed that flutamide, a specific AR antagonist, prevents complete Freund's adjuvant (CFA)-induced upregulation of MOR mRNA in TG, and that flutamide dose-dependently blocks the efficacy of DAMGO, a specific MOR agonist, on CFA-induced mechanical hypersensitivity. Our results expand the knowledge regarding the role of androgens and their receptor in pain and analgesia and have important clinical implications, particularly for inflammatory pain patients with low or compromised plasma testosterone levels.
University of Maryland School of Dentistry, Department of Neural and Pain Sciences, 650 W. Baltimore St., Baltimore, MD 21201, USA.
Ki Seok
KS
Lee
University of Maryland School of Dentistry, Department of Neural and Pain Sciences, 650 W. Baltimore St., Baltimore, MD 21201, USA.
Youping
Y
Zhang
University of Maryland School of Dentistry, Department of Neural and Pain Sciences, 650 W. Baltimore St., Baltimore, MD 21201, USA.
Jamila
J
Asgar
Kyung Hee University, School of Dentistry, Department of Oral Medicine, 1 Hoegi Dong, Dongdaemun Gu, Seoul, Republic of Korea.
Q-Schick
QS
Auh
University of Maryland School of Dentistry, Department of Neural and Pain Sciences, 650 W. Baltimore St., Baltimore, MD 21201, USA.
Man-Kyo
MK
Chung
University of Maryland School of Dentistry, Department of Neural and Pain Sciences, 650 W. Baltimore St., Baltimore, MD 21201, USA; Kyung Hee University, School of Dentistry, Department of Oral Medicine, 1 Hoegi Dong, Dongdaemun Gu, Seoul, Republic of Korea. Electronic address: jro@umaryland.edu.
Jin Y
JY
Ro
D000701:Analgesics, Opioid / Q000494:pharmacology; D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005485:Flutamide / Q000494:pharmacology; D005620:Freund's Adjuvant; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism*
D000701:Analgesics, Opioid; D059002:Androgen Receptor Antagonists; D012333:RNA, Messenger; D011944:Receptors, Androgen; D017450:Receptors, Opioid, mu; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005485:Flutamide; D005620:Freund's Adjuvant
flutamide; inflammation; peripheral; sensory neurons; testosterone