Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. The opioid epidemic in the USA has highlighted the need for alternative treatments for pain. Following reports on the opioid interactions of various antipsychotic medications, we speculated that the involvement of the opioid system in some of the antipsychotics’ mechanism of action may suggest their potential use in the treatment of pain. Risperidone is a neuroleptic with a potent dopamine D2 and serotonin 5-HT2 receptor-blocking activity as well as a high affinity for adrenergic and histamine H1 receptors. Amisulpride is a neuroleptic which selectively blocks dopamine D2 and D3 receptors. Both had a potent antinociceptive effect on ICR mice tested with a tail flick assay. That effect on both medications was antagonized by naloxone, indicating that at least some of the antinociceptive effects were mediated by an opioid mechanism of action. Further investigation found that β-Funaltrexamine hydrochloride (β-FNA), naloxonazine, and nor-Binaltorphimine dihydrochloride (nor-BNI) reversed the antinociceptive effect of both risperidone and amisulpride. Naltrindole at a dose that blocked [D-Pen2,D-Pen5]enkephalin (DPDPE, δ analgesia) blocked notably amisplride effect and only partially reversed that of risperidone. Risperidone induced an antinociceptive effect, implying involvement of μ and κ-opioid and δ-opioid mechanisms. Amisulpride-induced antinociception was mediated through selective involvement of all three opioid receptor subtypes. These findings emphasize the need for clinical trials to assess the possibility of extending the spectrum of medications available for the treatment of pain.

疼痛被定义为与实际或潜在组织损伤相关的不愉快的感觉和情绪体验。美国的阿片类药物流行凸显了对疼痛替代疗法的需求。根据关于各种抗精神病药物的阿片类药物相互作用的报告，我们推测阿片类药物系统参与某些抗精神病药物的作用机制可能表明它们在治疗疼痛中的潜在用途。利培酮是一种精神安定药，具有强效的多巴胺 D2 和血清素 5-HT2 受体阻断活性，以及​​对肾上腺素能和组胺 H1 受体的高亲和力。氨磺必利是一种精神安定剂，可选择性阻断多巴胺 D2 和 D3 受体。两者都对用甩尾试验测试的 ICR 小鼠具有有效的镇痛作用。纳洛酮拮抗了这两种药物的作用，表明至少一些镇痛作用是由阿片类药物作用机制介导的。进一步调查发现，β-氟氨曲胺盐酸盐（β-FNA）、纳洛嗪和nor -Binaltorphimine dihydrochloride (nor-BNI) 逆转了利培酮和氨磺必利的镇痛作用。Naltrindole 在阻断 [D-Pen2,D-Pen5] 脑啡肽（DPDPE，δ 镇痛）的剂量下显着阻断了阿米普利特的作用，并且仅部分逆转了利培酮的作用。利培酮诱导了镇痛作用，这意味着涉及 μ 和 κ-阿片类药物和 δ-阿片类药物机制。氨磺必利诱导的镇痛作用是通过所有三种阿片受体亚型的选择性参与介导的。这些发现强调了临床试验的必要性，以评估扩展可用于治疗疼痛的药物范围的可能性。