Activation of GPR30 attenuates chronic pain-related anxiety in ovariectomized mice
Introduction
Pain is an unpleasant sensory and emotional experience essential for safety and associated with potential or actual tissue damage (McKelvey et al., 2013). However, chronic pain (also referred to as persistent pain) persists for a prolonged period and is usually caused by various diseases or abnormal conditions (Siddall and Cousins, 2004). Chronic pain is highly associated with mood disorders, such as anxiety and depression (Bardel et al., 2013, Blackburn-Munro and Blackburn-Munro, 2001, Rouwette et al., 2012). Patients suffering from chronic pain also experience emotional disorders, such as depression, associated with additional pain complaints and impairment (Smith, 1992). This condition suggests that emotional disorder and pain share similar biological pathways and neurotransmitters, which affect concurrent treatments (Blier and Abbott, 2001).
A recent survey revealed that women are more likely to suffer from chronic widespread pain than men (Fillingim et al., 2009). Postmenopausal women are more susceptible to arthralgia (Magliano, 2010), chronic back pain (Ulivieri, 2007), headache, and cervical/lumbar pain (Meriggiola et al., 2012) than men, suggesting the involvement of estrogen-related mechanisms in the occurrence of these conditions. In the central nervous system (CNS), estradiol (17-β-estradiol, E2) regulates many functionally unrelated processes in numerous tissues. In general, estradiol acts via soluble intracellular α or β receptors (ERα or ERβ). Once activated, these receptors translocate to the nucleus and function as ligand-dependent transcription factors (Hall et al., 2001). However, fast nongenomic effects are mediated by classic receptors (ERα and ERβ) and specific G-protein-coupled receptors (GPR30 and ER-X) (Abe et al., 2008, Revankar et al., 2005) that regulate ligand-gated ion channels and neurotransmitter transporters (Carrer et al., 2003, Chu et al., 2009, Dominguez et al., 2007, Grassi et al., 2009). The roles of ERα and ERβ within a particular neural network may be synergistic or antagonistic. Examples of the latter include the role of ERα to enhance, and ERβ to suppress, anxiety-like and aggressive behaviors (Handa et al., 2012). In our previous study, GPR30-mediated fast nongenomic neuroprotection has been associated with decreased NR2B-containing N-methyl-d-aspartate receptors (NMDARs) (Liu et al., 2012); GPR30 also elicit anxiolytic effects in ovariectomized (OVX) mice after stress (Tian et al., 2013). However, the effects of GPR30 on anxiety, particularly on chronic pain-related anxiety, remain unclear.
The amygdala is a brain region implicated in emotional processing; thus, the amygdala is involved in anxiety. Studies have reported that the basolateral amygdala (BLA) and the central nucleus of the amygdala (CeA) are critical circuit elements that control acute anxiety in mammalian brain (Likhtik et al., 2008, Tye et al., 2011). In addition, the amygdala is implicated in pain-related anxiety and depression and serves as an integrated center of affective and sensory components of pain signaling (Rouwette et al., 2012). The amygdala possibly switches chronic pain on and off and is involved in major depressive disorders (Hamilton et al., 2008, Sacher et al., 2012).
Glutamate is a major excitatory neurotransmitter and γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the CNS. Increased ratio of excitatory/inhibitory activities may lead to psychiatric disorders (Yates, 2011). GABAergic inhibition is essential for temporal modulation and maintenance of excitation/inhibition balance (Klausberger and Somogyi, 2008). GABA receptors are classified as GABAA, GABAB, and GABAC types. Among the three GABA receptors, GABAA receptors are the major inhibitors and most important in GABAergic inhibition. GABAA receptor agonists, such as benzodiazepines and barbiturates, can induce sedation, calmness, anxiolytic, and anticonvulsant effects (Backstrom et al., 2011). GABAA receptors consist of α, β, γ, δ, ɛ, θ, π, and ρ subunits (Olsen and Sieghart, 2008); these receptors are commonly classified by their α subunits. Approximately 15% to 20% of all GABAA receptors contain an α2 subunit, which exhibits antidepressant-like properties and mediates anxiolytic-like, reward-enhancing, and antihyperalgesic actions of diazepam (Engin et al., 2012).
In this study, putative anxiolytic and analgesic effects of GPR30 was investigated in two types of chronic pain models. The underlying mechanisms of GPR30 regulating neuronal circuit of amygdala were also investigated.
Section snippets
Materials
All chemicals were purchased from Sigma (St. Louis, MO) unless otherwise stated. G1 was purchased from Cayman Chemical (Ann Arbor, MI). G15 was purchased from Calbiochem (Darmstadt, Germany). Rabbit anti-NR2A, mouse anti-NR2B and rabbit anti-phosphorylated GluR1 at Ser845 (p-GluR1-845) antibodies were purchased from Millipore (Billerica, MA). Rabbit anti-GPR30, rabbit anti-GluR1 and mouse anti-PSD95 antibodies were purchased from Abcam (Cambridge, UK). Rabbit anti-GABAA-α2 antibody was
CFA-induced anxiety-like behavior increases GPR30 levels in the BLA of OVX mice
Estrogen levels in plasma and cortex were measured 3 weeks after OVX. Compared to naïve control mice, E2 levels in plasma were significant decreased in the OVX mice (2264 ± 211 pmol/L vs 1253 ± 152 pmol/L; T = 5.487, n = 6, p < 0.01). Hindpaw CFA injection is a kind of chronic inflammatory pain model; this treatment significantly reduced the time spent (T = 3.697, p < 0.01; Fig. 1A) and the entries (T = 3.795, p < 0.01; Fig. 1B) in open arms in EPM test as well as the time in central areas in OP test (T = 2.669, p <
Discussion
In present study, two kinds of pain models were used, i.e., hindpaw CFA injection-induced chronic inflammatory pain and CCI-induced neuropathic pain models. Three routes of drug administration were used to regulate the function of GPR30, namely subcutaneously (s.c.) injection of G1 or G15, BLA local microinjection of G1 or G15, and BLA local microinjection of shRNA for GPR30. We found that chronic pain was accompanied by evident anxiety-like behavior in the OVX mice. The membrane estrogen
Role of the funding source
This research was supported by National Natural Science Foundation of China, Nos. 31271126, 31271144, 2011KTCL03-12, and China National Funds for Distinguished Young Scientists (No. 81325022).
Conflict of interest
None declared.
Acknowledgement
The authors thanked Dr. Min Zhuo (University of Toronto) for the constructive discussion for this manuscript.
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These authors contributed equally to this work.