Microglial interleukin-1β in the ipsilateral dorsal horn inhibits the development of mirror-image contralateral mechanical allodynia through astrocyte activation in a rat model of inflammatory pain.
Damage on one side of the body can also result in pain on the contralateral unaffected side, called mirror-image pain (MIP). Currently, the mechanisms responsible for the development of MIP are unknown. In this study, we investigated the involvement of spinal microglia and interleukin-1β (IL-1β) in the development of MIP using a peripheral inflammatory pain model. After unilateral carrageenan injection, mechanical allodynia (MA) in both hind paws and the expression levels of spinal Iba-1, IL-1β, and GFAP were evaluated. Ipsilateral MA was induced beginning at 3 hours after carrageenan injection, whereas contralateral MA showed a delayed onset occurring 5 days after injection. A single intrathecal (i.t.) injection of minocycline, a tetracycline derivative that displays selective inhibition of microglial activation, or an interleukin-1 receptor antagonist (IL-1ra) on the day of carrageenan injection caused an early temporary induction of contralateral MA, whereas repeated i.t. treatment with these drugs from days 0 to 3 resulted in a long-lasting contralateral MA, which was evident in its advanced development. We further showed that IL-1β was localized to microglia and that minocycline inhibited the carrageenan-induced increases in spinal Iba-1 and IL-1β expression. Conversely, minocycline or IL-1ra pretreatment increased GFAP expression as compared with that of control rats. However, i.t. pretreatment with fluorocitrate, an astrocyte inhibitor, restored minocycline- or IL-1ra-induced contralateral MA. These results suggest that spinal IL-1β derived from activated microglia temporarily suppresses astrocyte activation, which can ultimately prevent the development of contralateral MA under inflammatory conditions. These findings imply that microglial IL-1β plays an important role in regulating the induction of inflammatory MIP.
Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, South Korea Department of Maxillofacial Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, South Korea Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences College of Natural Sciences, Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, South Korea Department of Acupuncture, Moxibustion & Meridian Research, Medical Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea Department of Physiology, Institute of Brain Research, Chungnam National University Medical School, Daejeon, South Korea Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.
Hoon-Seong
HS
Choi
Dae-Hyun
DH
Roh
Seo-Yeon
SY
Yoon
Ji-Young
JY
Moon
Sheu-Ran
SR
Choi
Soon-Gu
SG
Kwon
Suk-Yun
SY
Kang
Ho-Jae
HJ
Han
Hyun-Woo
HW
Kim
Alvin J
AJ
Beitz
Seog-Bae
SB
Oh
Jang-Hern
JH
Lee
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology*; D002351:Carrageenan / Q000633:toxicity; D002951:Citrates / Q000494:pharmacology; D004195:Disease Models, Animal; D007839:Functional Laterality / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000209:etiology / Q000517:prevention & control*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008911:Minocycline / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D066148:Spinal Cord Dorsal Horn / Q000166:cytology*
D002951:Citrates; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D009419:Nerve Tissue Proteins; D053573:Receptors, Interleukin-1 Type I; C007744:fluorocitrate; D002351:Carrageenan; D008911:Minocycline