Aromatase Inhibition Exacerbates Pain and Reactive Gliosis in the Dorsal Horn of the Spinal Cord of Female Rats Caused by Spinothalamic Tract Injury

Abstract

Central pain syndrome is characterized by severe and excruciating pain resulting from a lesion in the central nervous system. Previous studies have shown that estradiol decreases pain and that inhibitors of the enzyme aromatase, which synthesizes estradiol from aromatizable androgens, increases pain sensitivity. In this study we have assessed whether aromatase expression in the dorsal horns of the spinal cord is altered in a rat model of central pain syndrome, induced by the unilateral electrolytic lesion of the spinothalamic tract. Protein and mRNA levels of aromatase, as well as the protein and mRNA levels of estrogen receptors α and β, were increased in the dorsal horn of female rats after spinothalamic tract injury, suggesting that the injury increased estradiol synthesis and signaling in the dorsal horn. To determine whether the increased aromatase expression in this pain model may participate in the control of pain, mechanical allodynia thresholds were determined in both hind paws after the intrathecal administration of letrozole, an aromatase inhibitor. Aromatase inhibition enhanced mechanical allodynia in both hind paws. Because estradiol is known to regulate gliosis we assessed whether the spinothalamic tract injury and aromatase inhibition regulated gliosis in the dorsal horn. The proportion of microglia with a reactive phenotype and the number of glial fibrillary acidic protein-immunoreactive astrocytes were increased by the injury in the dorsal horn. Aromatase inhibition enhanced the effect of the injury on gliosis. Furthermore, a significant a positive correlation of mechanical allodynia and gliosis in the dorsal horn was detected. These findings suggest that aromatase is up-regulated in the dorsal horn in a model of central pain syndrome and that aromatase activity in the spinal cord reduces mechanical allodynia by controlling reactive gliosis in the dorsal horn.

The neuroprotective actions of oestradiol and oestrogen receptors

“…In the brains of birds and mammals, aromatase is involved in the regulation of synaptogenesis and synaptic plasticity 151,152 , neurogenesis 153,154 , reproductive behaviour 155 , aggressive behaviour 155 , pain processing 156,157 , auditory processing 158 , social communication 158 , affect and cognition [159][160][161] .…”

Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions

“…Under physiological conditions in the CNS, aromatase is expressed mainly by neurons (Azcoitia et al, 2011;Jakab et al, 1993;Stanic et al, 2014). Aromatase activity in neurons is regulated by excitatory synaptic transmission (Charlier et al, 2013;Saldanha et al, 2011) and is involved in the regulation of synaptic activity, synaptic plasticity, neurogenesis, pain sensitivity, mood, cognition and reproductive behavior (Cornil et al, 2013;Fester and Rune, 2014;Ghorbanpoor et al, 2014;Krentzel and Remage-Healey, 2015;Saldanha et al, 2011). After brain injury, aromatase expression is induced in reactive astrocytes in rodents (Carswell et al, 2005;Garcia-Segura et al, 1999;Zhang Q et al, 2014), and in reactive astrocytes and radial glia of birds (Duncan et al, 2013a;Peterson et al, 2004Peterson et al, , 2001.…”

“…Neuroinflammatory signals, most likely cytokines, are involved in the induction of the expression of aromatase by astrocytes (Duncan and Saldanha, 2011). The induction of aromatase in astrocytes, and the consequent increase in the local production of estradiol within the brain, has neuroprotective effects, reducing gliosis and neuronal death and promoting neurogenesis Duncan et al, 2013b;Garcia-Segura et al, 2003;Ghorbanpoor et al, 2014;Peterson et al, 2007;Saldanha et al, 2009Saldanha et al, , 2005Wynne et al, 2008).…”

Glial cells and energy balance

“…Indeed, astrocytes express receptors for estrogens, androgens and progesterone (Pfaff & Keiner 1973, Garcia-Segura et al 1996b, Melcangi et al 2001, Garcia-Ovejero et al 2005 and sex steroids are reported to modulate the glial response to HFD (Louwe et al 2012, Morselli et al 2014. Sex steroids exert neuroprotective effects in various brain regions, with glial cells participating in this phenomenon (Azcoitia et al 2003, Garcia-Ovejero et al 2005, Barreto et al 2009, Ghorbanpoor et al 2014); thus, it is possible that sex hormones could protect against the deleterious effects of HFD-induced obesity on hypothalamic metabolic neuronal circuits by actions on the neighboring glia.…”