Sex-Dependent Glial Signaling in Pathological Pain: Distinct Roles of Spinal Microglia and Astrocytes

Abstract

Increasing evidence suggests that spinal microglia regulate pathological pain in males. In this study, we investigated the effects of several microglial and astroglial modulators on inflammatory and neuropathic pain following intrathecal injection in male and female mice. These modulators were the microglial inhibitors minocycline and ZVEID (a caspase-6 inhibitor) and the astroglial inhibitors L-α-aminoadipate (L-AA, an astroglial toxin) and carbenoxolone (a connexin 43 inhibitor), as well as U0126 (an ERK kinase inhibitor) and D-JNKI-1 (a c-Jun N-terminal kinase inhibitor). We found that spinal administration of minocycline or ZVEID, or Caspase6 deletion, reduced formalin-induced inflammatory and nerve injury-induced neuropathic pain primarily in male mice. In contrast, intrathecal L-AA reduced neuropathic pain but not inflammatory pain in both sexes. Intrathecal U0126 and D-JNKI-1 reduced neuropathic pain in both sexes. Nerve injury caused spinal upregulation of the astroglial markers GFAP and Connexin 43 in both sexes. Collectively, our data confirmed male-dominant microglial signaling but also revealed sex-independent astroglial signaling in the spinal cord in inflammatory and neuropathic pain.

Overexpression of P2X4 receptor in Schwann cells promotes motor and sensory functional recovery and remyelination via BDNF secretion after nerve injury

“…PL, TS, and IT were measured for at least four left and four right footprints per mouse. For testing mechanical sensitivity, a series of von Frey hairs with logarithmically increasing stiffness (0.02–2.56 g, Stoelting) were used as previously reported (Chen, Luo, Qadri, Berta, & Ji, ). We determined the 50% paw withdrawal threshold by the Dixon's up–down method.…”

“…In brief, the plantar surface of the hind paws of each mouse was painted with black ink and each mouse was led to walk in a straight path on a sheet of white paper. P2X2 ATCGGGGTGGGCTCCTTTCTG TCCCATATGCTGGTCAAGAGTGTC 324 P2X3 TCTCCTACTTTGTGGGGTGG TGATGACAAAGACAGAGGT GC 174 P2X4 TTGGCTCTGGCTTGGCGCTC TCTCCGGAAAGACCCTGCTCG 139 P2X5 GGGTTTCAGTTGGTTTCC GCTCTTCCCTAAGTTGTTTT 375 P2X6 TGTTACCGAGAGAGAACCAAGGAT GCTTTGGCAAGCTTTACTT CAGCA 250 P2X7 GTGTTGAAGGGATTGTTAGG GCTGGCTCAGGTTGATTAC 582 GAPDH AGACAGCCGCATCTTCTTGT TACTCAGCACCAGCATCACC 323 stiffness (0.02-2.56 g, Stoelting) were used as previously reported (Chen, Luo, Qadri, Berta, & Ji, 2018). We determined the 50% paw withdrawal threshold by the Dixon's up-down method.…”

Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice

“…For example, spinal TLR4 modulates inflammatory and neuropathic pain only in male mice (Sorge et al, 2011). Intrathecal injection of a microglial inhibitor (such as minocycline) attenuated mechanical allodynia in male but not female mice following peripheral nerve injury (Chen et al, 2017; Sorge et al, 2015). However, morphological activation of microglia (microgliosis) is not evident in male rodent models of chronic post-ischemia pain and chemotherapy-induced neuropathy (Robinson et al, 2014; Tian et al, 2017).…”

Recent Progress in Understanding the Mechanisms of Pain and Itch: the Second Special Issue

“…Chen and collaborators compare sexual dimorphism in microglial and astroglial signaling in the spinal cord. Their findings show that spinal microglia regulate inflammatory and neuropathic pain only in male mice, while spinal astrocytes regulate neuropathic pain in both sexes [35].…”