Integrated behavioral paradigms such as nociceptive processing coupled to anti-nociceptive responsiveness include systemically-mediated states of alertness, vigilance, motivation, and avoidance. Within a historical and cultural context, opium and its biologically active compounds, codeine and morphine, have been widely used as frontline anti-nociceptive agents. In eukaryotic cells, opiate alkaloids and opioid peptides were evolutionarily fashioned as regulatory factors in neuroimmune, vascular immune, and systemic immune communication and auto-immunoregulation. The significance of opioidergic regulation of immune function was validated by the identification of novel μ and δ opioid receptors on circulating leukocytes. The novel μ3 opioid receptor subtype has been characterized as an opioid peptide-insensitive and opiate alkaloid-selective G protein-coupled receptor (GPCR) that is functionally linked to the activation of constitutive nitric oxide synthase (cNOS). Opioid peptides stimulate granulocyte and immunocyte activation and chemotaxis via activation of a novel leukocyte δ2 receptor subtype. However, opiate alkaloid μ3 receptor agonists inhibit these same cellular activities. Opiate coupling to cNOS and subsequent production and release of mitochondrial nitric oxide (NO) suggests an evolutionary linkage to similar physiological events in prokaryotic cells. A subpopulation of immunocytes from Mytilus edulis and Leucophaea maderae and human granulocytes respond to low opioid concentrations, mediated by the adherence-promoting role of (D-Ala2-D-Met5)-enkephalinamide (DAMA), which is blocked by naloxone in a dose-dependent manner. Neutral endopeptidase 24.11 (NEP), or enkephalinase (CD10), is present on both human and invertebrate immunocytes. Alkaloids, including morphine, are found in both prokaryotic and eukaryotic cells and may have evolved much later in evolution through horizontal gene transfer. It is possible that opioid-mediated regulatory activities were conserved and elaborated during evolution as the central nervous system (CNS) became immunologically isolated by the blood-brain barrier. Thus, opioid receptor coupling became significant for cognitive and behavioural processes. Although opioid peptides and alkaloids work synergistically to suppress nociception, they mediate different actions in immune surveillance. Increased understanding of the evolutionary development of opioid receptors, nociceptive and anti-nociceptive pathways, and immunomodulation may help in the understanding of the development of tolerance to the clinical use of opiates for pain management. The significance of endogenous morphine’s importance to evolution can be ascertained by the number of physiological tissues and systems that can be affected by this chemical messenger mechanism, which transcends pain. An integrated review is presented of opioid and opiate receptors, immunomodulation, and pain associated with inflammation, from an evolutionary perspective.

综合行为范式，例如与抗伤害反应相结合的伤害性处理，包括系统介导的警觉、警觉、动机和回避状态。在历史和文化背景下，鸦片及其生物活性化合物可待因和吗啡已被广泛用作一线抗伤害性药物。在真核细胞中，阿片生物碱和阿片肽被进化为神经免疫、血管免疫、全身免疫通讯和自身免疫调节的调节因子。通过鉴定循环白细胞上的新型 μ 和 δ 阿片受体，验证了阿片能调节免疫功能的重要性。新型 μ3 阿片受体亚型已被表征为阿片肽不敏感和阿片生物碱选择性 G 蛋白偶联受体 (GPCR)，其在功能上与组成型一氧化氮合酶 (cNOS) 的激活有关。阿片肽通过激活新的白细胞 δ2 受体亚型来刺激粒细胞和免疫细胞的激活和趋化性。然而，阿片生物碱 μ3 受体激动剂会抑制这些相同的细胞活性。阿片类药物与 cNOS 的偶联以及随后线粒体一氧化氮 (NO) 的产生和释放表明与原核细胞中类似生理事件的进化联系。来自免疫细胞的亚群 阿片肽通过激活新的白细胞 δ2 受体亚型来刺激粒细胞和免疫细胞的激活和趋化性。然而，阿片生物碱 μ3 受体激动剂会抑制这些相同的细胞活性。阿片类药物与 cNOS 的偶联以及随后线粒体一氧化氮 (NO) 的产生和释放表明与原核细胞中类似生理事件的进化联系。来自免疫细胞的亚群 阿片肽通过激活新的白细胞 δ2 受体亚型来刺激粒细胞和免疫细胞的激活和趋化性。然而，阿片生物碱 μ3 受体激动剂会抑制这些相同的细胞活性。阿片类药物与 cNOS 的偶联以及随后线粒体一氧化氮 (NO) 的产生和释放表明与原核细胞中类似生理事件的进化联系。来自免疫细胞的亚群Mytilus edulis和Leucophaea maderae和人粒细胞对低阿片类药物浓度有反应，由 (D-Ala2-D-Met5)-脑啡肽 (DAMA) 的粘附促进作用介导，其被纳洛酮以剂量依赖性方式阻断。中性内肽酶 24.11 (NEP) 或脑啡肽酶 (CD10) 存在于人类和无脊椎动物免疫细胞上。包括吗啡在内的生物碱在原核和真核细胞中均有发现，并且可能在进化过程中通过水平基因转移进化得更晚。随着中枢神经系统 (CNS) 被血脑屏障免疫隔离，阿片类药物介导的调节活动可能在进化过程中得到保守和阐述。因此，阿片受体偶联对认知和行为过程变得重要。尽管阿片肽和生物碱协同作用抑制伤害感受，它们在免疫监视中介导不同的作用。对阿片受体、伤害性和抗伤害性通路以及免疫调节的进化发展的更多了解可能有助于了解对阿片类药物临床用于疼痛管理的耐受性的发展。内源性吗啡对进化的重要性可以通过受这种超越疼痛的化学信使机制影响的生理组织和系统的数量来确定。从进化的角度，对阿片类药物和阿片受体、免疫调节以及与炎症相关的疼痛进行了综合评价。和免疫调节可能有助于理解对阿片类药物临床用于疼痛管理的耐受性的发展。内源性吗啡对进化的重要性可以通过受这种超越疼痛的化学信使机制影响的生理组织和系统的数量来确定。从进化的角度，对阿片类药物和阿片受体、免疫调节以及与炎症相关的疼痛进行了综合评价。和免疫调节可能有助于理解对阿片类药物临床用于疼痛管理的耐受性的发展。内源性吗啡对进化的重要性可以通过受这种超越疼痛的化学信使机制影响的生理组织和系统的数量来确定。从进化的角度，对阿片类药物和阿片受体、免疫调节以及与炎症相关的疼痛进行了综合评价。