Department of Biological Structure, University of Washington, Seattle, USA.
Graduate Program in Neuroscience, University of Washington, Seattle, USA.
BMC Biol. 2023 Apr 3;21(1):69. doi: 10.1186/s12915-023-01573-7.
Pain is the primary reason people seek medical care, with chronic pain affecting ~ 20% of people in the USA. However, many existing analgesics are ineffective in treating chronic pain, while others (e.g., opioids) have undesirable side effects. Here, we describe the screening of a small molecule library using a thermal place aversion assay in larval zebrafish to identify compounds that alter aversion to noxious thermal stimuli and could thus serve as potential analgesics.
From our behavioral screen, we discovered a small molecule, Analgesic Screen 1 (AS1), which surprisingly elicited attraction to noxious painful heat. When we further explored the effects of this compound using other behavioral place preference assays, we found that AS1 was similarly able to reverse the negative hedonic valence of other painful (chemical) and non-painful (dark) aversive stimuli without being inherently rewarding. Interestingly, targeting molecular pathways canonically associated with analgesia did not replicate the effects of AS1. A neuronal imaging assay revealed that clusters of dopaminergic neurons, as well as forebrain regions located in the teleost equivalent of the basal ganglia, were highly upregulated in the specific context of AS1 and aversive heat. Through a combination of behavioral assays and pharmacological manipulation of dopamine circuitry, we determined that AS1 acts via D1 dopamine receptor pathways to elicit this attraction to noxious stimuli.
Together, our results suggest that AS1 relieves an aversion-imposed "brake" on dopamine release, and that this unique mechanism may provide valuable insight into the development of new valence-targeting analgesic drugs, as well as medications for other valence-related neurological conditions, such as anxiety and post-traumatic stress disorder (PTSD).
疼痛是人们寻求医疗的主要原因，美国约有 20%的人患有慢性疼痛。然而，许多现有的镇痛药在治疗慢性疼痛方面效果不佳，而其他药物（如阿片类药物）则有不良副作用。在这里，我们描述了使用幼虫斑马鱼热回避测定法筛选小分子文库，以鉴定改变对有害热刺激的厌恶并可作为潜在镇痛药的化合物。
从我们的行为筛选中，我们发现了一种小分子，镇痛筛选 1 号（AS1），它出人意料地引起了对有害热的吸引力。当我们使用其他行为位置偏好测定法进一步研究该化合物的作用时，我们发现 AS1 同样能够逆转其他疼痛（化学）和非疼痛（黑暗）厌恶刺激的负面愉悦价值，而没有内在的奖励。有趣的是，靶向与镇痛相关的分子途径并没有复制 AS1 的作用。神经元成像测定法显示，多巴胺能神经元簇以及位于硬骨鱼中脑基底神经节等效物的前脑区域在 AS1 和有害热的特定环境中高度上调。通过行为测定法和多巴胺通路的药理学操纵相结合，我们确定 AS1 通过 D1 多巴胺受体途径发挥作用，从而引起对有害刺激的这种吸引力。
总之，我们的结果表明，AS1 缓解了对多巴胺释放的厌恶施加的“刹车”，这种独特的机制可能为开发新的靶向效价的镇痛药以及其他与效价相关的神经疾病（如焦虑和创伤后应激障碍（PTSD））的药物提供有价值的见解。
