TY - JOUR
T1 - Sex-dependent pain trajectories induced by prolactin require an inflammatory response for pain resolution
AU - Mecklenburg, Jennifer
AU - Wangzhou, Andi
AU - Hovhannisyan, Anahit H.
AU - Barba-Escobedo, Priscilla
AU - Shein, Sergey A.
AU - Zou, Yi
AU - Weldon, Korri
AU - Lai, Zhao
AU - Goffin, Vincent
AU - Dussor, Gregory
AU - Tumanov, Alexei V.
AU - Price, Theodore J.
AU - Akopian, Armen N.
N1 - Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/3
Y1 - 2022/3
N2 - Pain development and resolution patterns in many diseases are sex-dependent. This study aimed to develop pain models with sex-dependent resolution trajectories, and identify factors linked to resolution of pain in females and males. Using different intra-plantar (i.pl.) treatment protocols with prolactin (PRL), we established models with distinct, sex-dependent patterns for development and resolution of pain. An acute PRL-evoked pain trajectory, in which hypersensitivity is fully resolved within 1 day, showed substantial transcriptional changes after pain-resolution in female and male hindpaws and in the dorsal root ganglia (DRG). This finding supports the notion that pain resolution is an active process. Prolonged treatment with PRL high dose (1 μg) evoked mechanical hypersensitivity that resolved within 5–7 days in mice of both sexes and exhibited a pro-inflammatory transcriptional response in the hindpaw, but not DRG, at the time point preceding resolution. Flow cytometry analysis linked pro-inflammatory responses in female hindpaws to macrophages/monocytes, especially CD11b+/CD64+/MHCII+ cell accumulation. Prolonged low dose PRL (0.1 μg) treatment caused non-resolving mechanical hypersensitivity only in females. This effect was independent of sensory neuronal PRLR and was associated with a lack of immune response in the hindpaw, although many genes underlying tissue damage were affected. We conclude that different i.pl. PRL treatment protocols generates distinct, sex-specific pain hypersensitivity resolution patterns. PRL-induced pain resolution is preceded by a pro-inflammatory macrophage/monocyte-associated response in the hindpaws of mice of both sexes. On the other hand, the absence of a peripheral inflammatory response creates a permissive condition for PRL-induced pain persistency in females.
AB - Pain development and resolution patterns in many diseases are sex-dependent. This study aimed to develop pain models with sex-dependent resolution trajectories, and identify factors linked to resolution of pain in females and males. Using different intra-plantar (i.pl.) treatment protocols with prolactin (PRL), we established models with distinct, sex-dependent patterns for development and resolution of pain. An acute PRL-evoked pain trajectory, in which hypersensitivity is fully resolved within 1 day, showed substantial transcriptional changes after pain-resolution in female and male hindpaws and in the dorsal root ganglia (DRG). This finding supports the notion that pain resolution is an active process. Prolonged treatment with PRL high dose (1 μg) evoked mechanical hypersensitivity that resolved within 5–7 days in mice of both sexes and exhibited a pro-inflammatory transcriptional response in the hindpaw, but not DRG, at the time point preceding resolution. Flow cytometry analysis linked pro-inflammatory responses in female hindpaws to macrophages/monocytes, especially CD11b+/CD64+/MHCII+ cell accumulation. Prolonged low dose PRL (0.1 μg) treatment caused non-resolving mechanical hypersensitivity only in females. This effect was independent of sensory neuronal PRLR and was associated with a lack of immune response in the hindpaw, although many genes underlying tissue damage were affected. We conclude that different i.pl. PRL treatment protocols generates distinct, sex-specific pain hypersensitivity resolution patterns. PRL-induced pain resolution is preceded by a pro-inflammatory macrophage/monocyte-associated response in the hindpaws of mice of both sexes. On the other hand, the absence of a peripheral inflammatory response creates a permissive condition for PRL-induced pain persistency in females.
KW - DRG
KW - Inflammation
KW - Pain resolution
KW - Prolactin
KW - Sex-difference
KW - Skin
UR - http://www.scopus.com/inward/record.url?scp=85123081847&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123081847&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2022.01.016
DO - 10.1016/j.bbi.2022.01.016
M3 - Article
C2 - 35065194
AN - SCOPUS:85123081847
SN - 0889-1591
VL - 101
SP - 246
EP - 263
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -