Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
BMC Cancer. 2021 Oct 20;21(1):1128. doi: 10.1186/s12885-021-08850-0.
Clinically, the coadministration of opioids to enhance antinociception and decrease tolerance has attracted increasing research attention. We investigated the effects of dezocine, a mu- and kappa-opioid receptor agonist/antagonist, on morphine tolerance and explored the involvement of opioid receptor expression in a rat model of bone cancer pain.
Thermal nociceptive thresholds were measured after the subcutaneous injection of morphine (10 mg/kg) alone or combined with dezocine (10 or 1 mg/kg) for 7 consecutive days. Real-time PCR and western blot analysis were used to examine opioid receptor expression in the periaqueductal gray (PAG) and spinal cord.
The analgesic effect was significantly decreased after 4 days of morphine administration. We observed that low-dose dezocine significantly attenuated morphine tolerance without reducing the analgesic effect of morphine. Low-dose dezocine coadministration significantly reversed the downregulated expression of mu (MOR) and delta (DOR) opioid receptors in the PAG and the upregulated expression of kappa (KOR) and DOR in the spinal cord induced by morphine. Moreover, low-dose dezocine coadministered with morphine significantly inhibited KOR expression in both the PAG and spinal cord.
The combination of low-dose dezocine with morphine may prevent or delay the development of morphine tolerance in a rat model of bone cancer pain. The regulation of opioid receptor expression in the PAG and spinal cord may be part of the mechanism.
临床上，联合应用阿片类药物增强镇痛作用和减少耐受性引起了越来越多的研究关注。我们研究了地佐辛（一种 μ 和 κ 阿片受体激动剂/拮抗剂）对吗啡耐受的影响，并探讨了在骨癌痛大鼠模型中阿片受体表达的参与情况。
皮下注射吗啡（10mg/kg）单独或联合地佐辛（10 或 1mg/kg）连续 7 天，测量热痛觉阈值。采用实时 PCR 和 Western blot 分析检测periaqueductal gray（PAG）和脊髓中阿片受体的表达。
吗啡给药 4 天后，镇痛效果明显下降。我们观察到，低剂量地佐辛可显著减轻吗啡耐受，而不降低吗啡的镇痛效果。低剂量地佐辛与吗啡联合应用可显著逆转吗啡诱导的 PAG 中 μ（MOR）和 δ（DOR）阿片受体表达下调以及脊髓中 κ（KOR）和 DOR 表达上调。此外，低剂量地佐辛与吗啡联合应用可显著抑制 PAG 和脊髓中 KOR 的表达。
在骨癌痛大鼠模型中，低剂量地佐辛与吗啡联合应用可能预防或延迟吗啡耐受的发生。PAG 和脊髓中阿片受体表达的调节可能是其机制的一部分。
