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.
Highlights
Opiates acting at the μ-opioid receptor have been the most effective and most commonly used analgesics to treat severe pain conditions, e.g., neuropathic and inflammation-induced pain
We recently reported that NOP-mediated thermal antinociception in an acute pain model was quickly diminished following the activation of membrane estrogen receptors GPR30, Gq-mER, and ERα, but not ERβ [18]
In OVX animals, spared nerve injury (SNI) led to a significant reduction in paw withdrawal thresholds (PWTs) throughout the time course compared to the sham group (F(130,429) = 2.18; p < 0.05), which was indicative of nerve injury-induced tactile hypersensitivity (Figure 1a)
Summary
Opiates acting at the μ-opioid receptor have been the most effective and most commonly used analgesics to treat severe pain conditions, e.g., neuropathic and inflammation-induced pain. They are associated with many adverse side effects, including tolerance, dependence, and constipation [1]. Preclinical studies have shown that activation of the NOP receptor is associated with fewer deleterious side effects than that of other opioid receptors [4,5,6]. The NOP, as well as its endogenous ligand N/OFQ, is expressed in the dorsal horn of the spinal cord and other pain processing areas of the brain [2,3,7].
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