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Activation of Membrane Estrogen Receptors Attenuates NOP-Mediated Tactile Antihypersensitivity in a Rodent Model of Neuropathic Pain

Department of Biochemistry, Cancel Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA
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Brain Sci. 2019, 9(6), 147; https://doi.org/10.3390/brainsci9060147
Received: 31 May 2019 / Revised: 16 June 2019 / Accepted: 19 June 2019 / Published: 21 June 2019
(This article belongs to the Special Issue Sex Differences in the Brain: The Estrogen Quandary)
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Abstract

Women manifest a higher prevalence of several chronic pain disorders compared to men. We demonstrated earlier that estrogen rapidly attenuates nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP)-mediated thermal antinociception through the activation of membrane estrogen receptors (mERs). However, the effect of mER activation on NOP-mediated attenuation of tactile hypersensitivity in a neuropathic model of pain and the underlying mechanisms remain unknown. Following spared nerve injury (SNI), male and ovariectomized (OVX) female rats were intrathecally (i.t.) injected with a selective mER agonist and nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for NOP, and their effects on paw withdrawal thresholds (PWTs) were tested. In addition, spinal cord tissue was used to measure changes in phosphorylated extracellular signal regulated kinase (ERK), protein kinase A (PKA), protein kinase C (PKC), and protein kinase B (Akt) levels. SNI significantly reduced PWTs in males and OVX females, indicating tactile hypersensitivity. N/OFQ restored PWTs, indicating an antihypersensitive effect. Selective mER activation attenuated the effect of N/OFQ in an antagonist-reversible manner. SNI led to a robust increase in the phosphorylation of ERK, PKA, PKC, and Akt. However, mER activation did not further affect it. Thus, we conclude that activation of mERs rapidly abolishes NOP-mediated tactile antihypersensitivity following SNI via an ERK-, PKA-, PKC-, and Akt-independent mechanism. View Full-Text
Keywords: nociceptin/orphanin FQ receptor; neuropathic pain; spinal cord; spared nerve injury; analgesia nociceptin/orphanin FQ receptor; neuropathic pain; spinal cord; spared nerve injury; analgesia
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Wright, D.M.; Small, K.M.; Nag, S.; Mokha, S.S. Activation of Membrane Estrogen Receptors Attenuates NOP-Mediated Tactile Antihypersensitivity in a Rodent Model of Neuropathic Pain. Brain Sci. 2019, 9, 147.

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