title: Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain.
abstract: Prolactin (PRL) is a hormone produced in the anterior pituitary but also synthesized extrapituitary where it can influence diverse cellular processes, including inflammatory responses. Females experience greater pain in certain inflammatory conditions, but the contribution of the PRL system to sex-dependent inflammatory pain is unknown. We found that PRL regulates transient receptor potential (TRP) channels in a sex-dependent manner in sensory neurons. At >20 ng/ml, PRL sensitizes TRPV1 in female, but not male, neurons. This effect is mediated by PRL receptor (PRL-R). Likewise, TRPA1 and TRPM8 were sensitized by 100 ng/ml PRL only in female neurons. We showed that complete Freund adjuvant (CFA) upregulated PRL levels in the inflamed paw of both male and female rats, but levels were higher in females. In contrast, CFA did not change mRNA levels of long and short PRL-R in the dorsal root ganglion or spinal cord. Analysis of PRL and PRL-R knockout (KO) mice demonstrated that basal responses to cold stimuli were only altered in females, and with no significant effects on heat and mechanical responses in both sexes. CFA-induced heat and cold hyperalgesia were not changed in PRL and PRL-R KO compared with wild-type (WT) males, whereas significant reduction of heat and cold post-CFA hyperalgesia was detected in PRL and PRL-R KO females. Attenuation of CFA-induced mechanical allodynia was observed in both PRL and PRL-R KO females and males. Thermal hyperalgesia in PRL KO females was restored by administration of PRL into hindpaws. Overall, we demonstrate a sex-dependent regulation of peripheral inflammatory hyperalgesia by the PRL system.
authors.affiliation: Department of Pharmacology University of Texas Health Science Center at San Antonio, San Antonio, Texas; and.
authors.forename: Mayur J
authors.initials: MJ
authors.lastname: Patil
authors.forename: Shivani B
authors.initials: SB
authors.lastname: Ruparel
authors.forename: Michael A
authors.initials: MA
authors.lastname: Henry
authors.forename: Armen N
authors.initials: AN
authors.lastname: Akopian
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003080:Cold Temperature; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology; D007249:Inflammation / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000473:pathology*; D010812:Physical Stimulation; D011388:Prolactin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011981:Receptors, Prolactin / Q000187:drug effects / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D012727:Sex Characteristics; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000187:drug effects / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000187:drug effects / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000187:drug effects / Q000378:metabolism*
chemical_list: D011981:Receptors, Prolactin; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050053:TRPM Cation Channels; D050916:TRPV Cation Channels; C480976:Trpa1 protein, rat; C498947:Trpm8 protein, rat; C493922:Trpv1 protein, rat; D011388:Prolactin
keywords: female; inflammation; pain; prolactin receptor; transient receptor potential A1; transient receptor potential M8; transient receptor potential V1
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18820-4
references.pmid: 19843694
references.citation: FEBS Lett. 2001 Jan 12;488(1-2):91-4
references.pmid: 11163802
references.citation: Life Sci. 1996;59(8):599-614
references.pmid: 8761011
references.citation: J Clin Invest. 2013 Sep;123(9):3902-13
references.pmid: 23908112
references.citation: Pain. 2000 Mar;85(1-2):93-9
references.pmid: 10692607
references.citation: J Mol Endocrinol. 2003 Feb;30(1):31-47
references.pmid: 12580759
references.citation: Mol Cell Biol. 2009 May;29(10):2546-55
references.pmid: 19273600
references.citation: J Pain. 2009 May;10(5):447-85
references.pmid: 19411059
references.citation: Rev Recent Clin Trials. 2011 Jan;6(1):52-63
references.pmid: 20868350
references.citation: Eur J Pain. 2011 Apr;15(4):376-83
references.pmid: 20932788
references.citation: J Neurosci. 2006 Aug 2;26(31):8126-36
references.pmid: 16885226
references.citation: Nat Med. 2003 Nov;9(11):1383-9
references.pmid: 14528299
references.citation: Neuroscience. 2008 Aug 13;155(2):503-9
references.pmid: 18582539
references.citation: J Physiol. 2003 Sep 1;551(Pt 2):433-46
references.pmid: 12815188
references.citation: Cell. 2006 Mar 24;124(6):1269-82
references.pmid: 16564016
references.citation: Curr Protoc Neurosci. 2009 Jul;Appendix 4:Appendix 4I
references.pmid: 19575469
references.citation: Genes Dev. 1997 Jan 15;11(2):167-78
references.pmid: 9009200
references.citation: Mol Endocrinol. 2006 Aug;20(8):1912-23
references.pmid: 16556730
references.citation: Am J Physiol Endocrinol Metab. 2004 Oct;287(4):E750-7
references.pmid: 15186999
references.citation: J Rheumatol. 2000 Sep;27(9):2160-5
references.pmid: 10990228
references.citation: Nature. 2007 Jul 12;448(7150):204-8
references.pmid: 17538622
references.citation: J Neurosci. 1987 Jan;7(1):77-87
references.pmid: 3027278
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10150-5
references.pmid: 12097645
references.citation: Science. 2000 Oct 6;290(5489):124-7
references.pmid: 11021795
references.citation: J Biol Chem. 2003 Sep 19;278(38):35988-99
references.pmid: 12824168
references.citation: Endocrinology. 1999 Jan;140(1):96-105
references.pmid: 9886812
references.citation: Science. 1988 Jan 22;239(4838):401-4
references.pmid: 3122324
references.citation: Endocrinology. 2012 Nov;153(11):5612-21
references.pmid: 23011923
references.citation: J Pharmacol Exp Ther. 2005 Apr;313(1):449-59
references.pmid: 15608071
references.citation: J Rheumatol. 2012 Jun;39(6):1221-30
references.pmid: 22505697
references.citation: Neuroscience. 2013 Sep 17;248:552-61
references.pmid: 23830906
references.citation: Am J Manag Care. 2001 Oct;7(16 Suppl):S486-9
references.pmid: 11680780
references.citation: J Rheumatol. 1998 Nov;25(11):2077-82
references.pmid: 9818647
references.citation: Neuroimmunomodulation. 2011;18(4):245-53
references.pmid: 21430396
references.citation: Biol Reprod. 2007 May;76(5):777-83
references.pmid: 17267700
references.citation: J Biol Chem. 2006 Oct 27;281(43):32879-90
references.pmid: 16954222
references.citation: Rheumatology (Oxford). 2002 Apr;41(4):423-9
references.pmid: 11961173
references.citation: Neuron. 2004 Mar 25;41(6):849-57
references.pmid: 15046718
references.citation: Brain Res. 2002 Oct 11;952(1):15-30
references.pmid: 12363400
references.citation: Lupus. 2001;10(10):706-18
references.pmid: 11721697
references.citation: Endocr Rev. 1998 Jun;19(3):225-68
references.pmid: 9626554
references.citation: Neuron. 2006 Apr 20;50(2):277-89
references.pmid: 16630838
references.citation: J Neurosci. 2006 Aug 16;26(33):8588-99
references.pmid: 16914685
references.citation: FASEB J. 2002 Oct;16(12):1497-503
references.pmid: 12374772
references.citation: Neuropsychiatr Dis Treat. 2011;7:611-20
references.pmid: 22090797
references.citation: Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1471-5
references.pmid: 9037077
references.citation: J Sex Res. 2010 Mar;47(2):153-70
references.pmid: 20358458
references.citation: Pain. 2012 Oct;153(10):2031-2039
references.pmid: 22633978
references.citation: J Neurosci. 2012 Jun 6;32(23):8074-83
references.pmid: 22674282
references.citation: Physiol Behav. 1993 Feb;53(2):265-70
references.pmid: 8383345
references.citation: Mol Endocrinol. 2011 Nov;25(11):1892-903
references.pmid: 21903722
references.citation: Pain. 1988 Jan;32(1):77-88
references.pmid: 3340425
references.citation: Immunology. 1992 Nov;77(3):449-55
references.pmid: 1478689
references.citation: Int Rev Neurobiol. 2011;97:179-206
references.pmid: 21708311
references.citation: J Endocrinol. 2011 Feb;208(2):107-17
references.pmid: 21068074
references.citation: Curr Opin Urol. 2011 Nov;21(6):527-34
references.pmid: 21941183
references.citation: Mol Cell Biochem. 2008 Jun;313(1-2):147-53
references.pmid: 18401558
references.citation: Neuroscience. 2007 Mar 30;145(3):963-73
references.pmid: 17317019
references.citation: Br J Rheumatol. 1997 Apr;36(4):426-32
references.pmid: 9159534
references.citation: J Physiol. 2007 Aug 15;583(Pt 1):175-93
references.pmid: 17584831
references.citation: Mol Cell Endocrinol. 1997 Apr 4;128(1-2):117-27
references.pmid: 9140083
references.citation: Nature. 2002 Mar 7;416(6876):52-8
references.pmid: 11882888
references.citation: Lupus. 1998;7(6):383-6
references.pmid: 9736320
references.citation: EMBO J. 1997 Dec 1;16(23):6926-35
references.pmid: 9384572
references.citation: Crit Rev Oral Biol Med. 2000;11(1):57-91
references.pmid: 10682901
references.citation: Science. 2000 Apr 14;288(5464):306-13
references.pmid: 10764638
references.citation: Neuron. 2007 May 3;54(3):379-86
references.pmid: 17481392
references.citation: Arthritis Rheum. 1984 Jun;27(6):682-8
references.pmid: 6329236
references.citation: J Pharmacol Exp Ther. 1999 Aug;290(2):678-86
references.pmid: 10411578
references.citation: J Clin Invest. 2007 Jul;117(7):1979-87
references.pmid: 17571167
references.citation: Pain. 2011 May;152(5):1146-1155
references.pmid: 21396782
references.citation: J Neurosci Res. 2002 Feb 15;67(4):551-8
references.pmid: 11835322
references.citation: Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6721-6
references.pmid: 22493235
references.citation: Trends Endocrinol Metab. 1993 Jul;4(5):147-51
references.pmid: 18407149
references.citation: Ann Surg. 2010 May;251(5):923-31
references.pmid: 20395845
references.citation: Eur J Neurosci. 2011 Sep;34(5):745-54
references.pmid: 21777304
references.citation: Pituitary. 2005;8(1):25-30
references.pmid: 16411065