A novel small molecule, AS1, reverses the negative hedonic valence of noxious stimuli

Background Pain is the primary reason people seek medical care, with chronic pain affecting similar to 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. Results 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. Conclusions 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).

Automated summary

Pain is one of the main reasons for seeking medical care, but current analgesics are often ineffective or have undesirable side effects. A small molecule called AS1 was discovered through a behavioral screen in larval zebrafish, which surprisingly elicited attraction to noxious heat. Further experiments showed that AS1 can reverse the negative valence of both painful and non-painful aversive stimuli without being rewarding. The mechanism of AS1 involves the activation of D1 dopamine receptor pathways.