DPDPE is a selective and anticonvulsant δ-opioid receptor (DOR) agonist[1]. DOR is a G protein-coupled receptor (GPCR) primarily distributed in the central nervous system, which mediates various physiological effects such as analgesia and antidepressant actions of both endogenous enkephalins and exogenous ligands[2]. DPDPE is commonly used in studies involving opioid receptor signaling, pain pathways, and addiction mechanisms[3].
In vitro, treatment of HEK293 cells overexpressing or with knocked-down GRK2 with DPDPE (2μM) for 30min showed that GRK2 overexpression enhanced internalization and subsequent recycling of the wild-type receptor, whereas GRK2 knockdown inhibited these processes[4]. Pretreatment of HEK293 cells with DPDPE (1μM) for 60min induced only mild DOR desensitization, which was significantly enhanced in the presence of monensin[5]. Treatment of CHO cells stably expressing human DOR (CHO/DOR) with DPDPE (100nM) for 5-30min rapidly and significantly induced phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9, accompanied by a marked inhibition (~35%) of kinase activity[6].
In vivo, subcutaneous injection of DPDPE (0.5, 1, 3, 5mg/kg) in streptozotocin (STZ)-induced diabetic neuropathic mice produced dose-dependent inhibition of mechanical allodynia, thermal hyperalgesia, and thermal allodynia 30min after administration[7]. In Sprague Dawley rats, intrathecal pretreatment with DPDPE (100nM; 10μL) 10min before hindpaw compression significantly inhibited noxious stimulation-induced neurokinin 1 receptor (NK1R) internalization in lamina I of the spinal dorsal horn[8].
References:
[1] TORTELLA F C, ECHEVARRIA E, ROBLES L, et al. Anticonvulsant effects of mu (DAGO) and delta (DPDPE) enkephalins in rats[J]. Peptides, 1988, 9(5): 1177-1181.
[2] NIETO M M, GUEN S L E, KIEFFER B L, et al. Physiological control of emotion-related behaviors by endogenous enkephalins involves essentially the delta opioid receptors[J]. Neuroscience, 2005, 135(2): 305-313.
[3] ABDALLAH K, GENDRON L. The delta opioid receptor in pain control[J]. Delta Opioid Receptor Pharmacology and Therapeutic Applications. 2017: 147-177.
[4] ZHANG X, WANG F, CHEN X, et al. Post-endocytic fates of δ-opioid receptor are regulated by GRK2-mediated receptor phosphorylation and distinct β-arrestin isoforms[J]. Journal of Neurochemistry, 2008, 106(2): 781-792.
[5] AUDET N, CHARFI I, MNIE-FILALI O, et al. Differential association of receptor-Gβγ complexes with β-arrestin2 determines recycling bias and potential for tolerance of delta opioid receptor agonists[J]. Journal of Neuroscience, 2012, 32(14): 4827-4840.
[6] OLIANAS M C, DEDONI S, ONALI P. Signaling pathways mediating phosphorylation and inactivation of glycogen synthase kinase-3β by the recombinant human δ-opioid receptor stably expressed in Chinese hamster ovary cells[J]. Neuropharmacology, 2011, 60(7-8): 1326-1336.
[7] CASTANY S, CARCOLÉ M, LEÁNEZ S, et al. The antinociceptive effects of a δ-opioid receptor agonist in mice with painful diabetic neuropathy: Involvement of heme oxygenase 1[J]. Neuroscience Letters, 2016, 614: 49-54.
[8] KONDO I, MARVIZON J C G, SONG B, et al. Inhibition by spinal μ- and δ-opioid agonists of afferent-evoked substance P release[J]. Journal of Neuroscience, 2005, 25(14): 3651-3660.
DPDPE是一种具有选择性和抗惊厥作用的δ-阿片受体（DOR）激动剂[1]。DOR是一种主要分布于中枢神经系统的G蛋白偶联受体（GPCR），可介导内源性脑啡肽及外源性配体的镇痛、抗抑郁等多种生理效应[2]。DPDPE通常用于阿片受体信号传导、疼痛通路以及成瘾机制等领域的研究[3]。
在体外，DPDPE（2μM）处理过表达或敲低GRK2的HEK293细胞30min，过表达GRK2增强了野生型受体的内化和后续循环，敲低GRK2则抑制了内化和循环[4]。DPDPE（1μM）预处理HEK293细胞60min，仅引起轻度DOR脱敏，而在monensin存在情况下脱敏程度可被显著增强[5]。DPDPE（100nM）处理稳定表达人DOR的CHO细胞（CHO/DOR）5-30min，可迅速且显著诱导糖原合酶激酶-3β（GSK-3β）在Ser9位点的磷酸化，并伴随激酶活性显著抑制（约35%）[6]。
在体内，DPDPE（0.5, 1, 3, 5mg/kg）通过皮下注射治疗streptozotocin（STZ）诱导的糖尿病神经病变小鼠，30min后剂量依赖性地抑制了机械性异常疼痛、热痛觉过敏和热异常性疼痛[7]。DPDPE（100nM; 10μL）通过鞘内注射预处理Sprague Dawley大鼠10min，显著抑制了由后爪压迫性伤害刺激诱导的脊髓背角I层神经激肽1受体（NK1R）内化[8]。