Huang Peng, Ho Conrad K, Bland Kathryn, Liu-Chen Lee-Yuan
Center for Substance Abuse Research and Department of Neural Sciences, Lewis Katz School of Medicine, Temple University Philadelphia PA USA.
Center for Substance Abuse Research and Department of Neural Sciences, Lewis Katz School of Medicine, Temple University Philadelphia PA USA.
Neurosci Lett. 2025 Feb 28;850:138154. doi: 10.1016/j.neulet.2025.138154. Epub 2025 Feb 7.
We previously demonstrated that in a mouse line expressing a kappa opioid receptor (KOR) mutant with all the four phosphorylation sites mutated to alanines (K4A) the selective KOR agonist U50,488H (U50)-induced anti-scratching tolerance was attenuated in males and conditioned place aversion (CPA) was reduced in females, without affecting acute U50-induced anti-scratching effect and hypo-locomotion (Huang et al, 2022, Neuropharmacology). KOR phosphorylation deficiency in K4A mice would lead to little recruitment of β-arrestin2 (arrb2) and hence greatly reduced arrb2-mediated KOR regulation, downstream signaling and behaviors. Herein we examined effects of arrb2 deletion in mice on KOR-mediated behaviors in arrb2 knockout (arrb2(-/-)) mice vs wildtype (WT) mice. We found that arrb2 deletion enhanced anti-scratching effects produced by acute U50 in males, but not in females. Intriguingly, in ovariectomized (OVX) but not sham-operated females, arrb2 deletion increased U50-induced anti-scratching effect, similar to males. Furthermore, OVX enhanced U50-induced anti-scratching effects specifically in arrb2(-/-) females, but not in WT females. Thus, ovarian hormones-related modulations may obscure the phenotype associated with arrb2(-/-) to promote the KOR-mediated anti-scratching signaling in females, while OVX unmasked it. In contrast, arrb2 deletion did not affect U50-induced CPA and had no effects on anti-scratching tolerance to repeated U50 in either male or female mice. The findings in arrb2(-/-) mice revealed both similarities and differences compared to our previous results in K4A mice. Overall, the effects of arrb2 deletion on KOR-mediated behaviors depended on specific behavioral endpoints, sex, and OVX status.
我们之前证明，在一个表达κ阿片受体（KOR）突变体的小鼠品系中，该突变体的所有四个磷酸化位点都突变为丙氨酸（K4A），选择性KOR激动剂U50,488H（U50）诱导的抗抓挠耐受性在雄性小鼠中减弱，而条件性位置厌恶（CPA）在雌性小鼠中降低，且不影响U50诱导的急性抗抓挠效应和运动减少（Huang等人，2022年，《神经药理学》）。K4A小鼠中的KOR磷酸化缺陷会导致β-抑制蛋白2（arrb2）募集很少，从而大大降低arrb2介导的KOR调节、下游信号传导和行为。在此，我们研究了小鼠中arrb2缺失对野生型（WT）小鼠与arrb2基因敲除（arrb2(-/-)）小鼠中KOR介导行为的影响。我们发现，arrb2缺失增强了急性U50对雄性小鼠产生的抗抓挠效应，但对雌性小鼠没有影响。有趣的是，在去卵巢（OVX）而非假手术的雌性小鼠中，arrb2缺失增加了U50诱导的抗抓挠效应，与雄性小鼠相似。此外，OVX特别增强了U50对arrb2(-/-)雌性小鼠的抗抓挠效应，但对WT雌性小鼠没有影响。因此，卵巢激素相关的调节可能掩盖了与arrb2(-/-)相关的表型，以促进雌性小鼠中KOR介导的抗抓挠信号传导，而OVX则使其显现出来。相比之下，arrb2缺失不影响U50诱导的CPA，对雄性或雌性小鼠重复使用U50后的抗抓挠耐受性也没有影响。与我们之前在K4A小鼠中的结果相比，arrb2(-/-)小鼠的研究结果既有相似之处也有不同之处。总体而言，arrb2缺失对KOR介导行为的影响取决于特定的行为终点、性别和OVX状态。
