δ-Opioid Receptor and Somatostatin Receptor-4 Heterodimerization: Possible Implications in Modulation of Pain Associated Signaling

Pain relief is the principal action of opioids. Somatostatin (SST), a growth hormone inhibitory peptide is also known to alleviate pain even in cases when opioids fail. Recent studies have shown that mice are prone to sustained pain and devoid of analgesic effect in the absence of somatostatin receptor 4 (SSTR4). In the present study, using brain slices, cultured neurons and HEK-293 cells, we showed that SSTR4 and δ-Opioid receptor (δOR) exist in a heteromeric complex and function in synergistic manner. SSTR4 and δOR co-expressed in cortical/striatal brain regions and spinal cord. Using cultured neuronal cells, we describe the heterogeneous complex formation of SSTR4 and δOR at neuronal cell body and processes. Cotransfected cells display inhibition of cAMP/PKA and co-activation of SSTR4 and δOR oppose receptor trafficking induced by individual receptor activation. Furthermore, downstream signaling pathways either associated with withdrawal or pain relief are modulated synergistically with a predominant role of SSTR4. Inhibition of cAMP/PKA and activation of ERK1/2 are the possible cellular adaptations to prevent withdrawal induced by chronic morphine use. Our results reveal direct intra-membrane interaction between SSTR4 and δOR and provide insights for the molecular mechanism for the anti-nociceptive property of SST in combination with opioids as a potential therapeutic approach to avoid undesirable withdrawal symptoms.

阿片类药物的核心作用为镇痛。生长抑素（somatostatin, SST）作为一种生长激素抑制肽，即便在阿片类药物镇痛失效的场景中，同样可有效缓解疼痛。近期研究证实，缺失生长抑素受体4（somatostatin receptor 4, SSTR4）的小鼠易出现持续性疼痛，且无法产生镇痛效应。本研究借助脑切片、培养神经元及HEK-293细胞开展实验，结果显示SSTR4与δ-阿片受体（δ-Opioid receptor, δOR）以异源多聚体复合物形式存在，并以协同方式发挥功能。SSTR4与δOR在大脑皮层/纹状体脑区及脊髓中存在共表达现象。利用培养的神经元细胞，我们发现SSTR4与δOR的异源复合物可形成于神经元胞体及突起部位。共转染细胞的cAMP/PKA通路受到抑制，且SSTR4与δOR的共同激活可拮抗单一受体激活所诱导的受体转运过程。此外，与戒断反应或镇痛相关的下游信号通路均受到协同调控，其中SSTR4发挥主导作用。抑制cAMP/PKA通路并激活ERK1/2，或是慢性吗啡使用诱导戒断反应的潜在细胞适应机制。本研究结果揭示了SSTR4与δOR之间直接的膜内相互作用，为生长抑素联合阿片类药物发挥抗伤害感受特性的分子机制提供了全新见解，同时也为规避慢性吗啡治疗引发的不良戒断症状提供了潜在治疗策略。