Project Summary
Pain is the number one reason patients seek health care and greater than 20% of the US population is affected
by chronic pain. Existing therapeutics have limited efficacy and a narrow therapeutic period, while also evoking
deleterious side effects. It is therefore vital to understand pain processing in order to develop novel
therapeutics to address this pressing health care crisis. According to the International Association for the Study
of Pain (IASP) pain is “an unpleasant sensory and emotional experience associated with actual or potential
tissue damage”. Intrinsic to the emotional suffering elicited by pain perception is the attribution of a negative
valence to nociceptive stimuli. Dysregulation of aversive motivational circuits may underlie much of the
suffering associated with chronic pain conditions. Hedonic valence is a measurement of the intrinsic
attractiveness (positive) or averseness (negative) of a stimulus. Pain typically has a negative valence, which is
normally advantageous, driving self-protective behavior. Perversely, humans can sometimes assign a positive
valence to nociceptive stimuli; think pleasure from spicy foods. This implies that the neural circuits that assign
negative valence to nociceptive stimuli are malleable and that pain and aversion can be decoupled. Critically,
there have been limited tools to investigate how valence is assigned to nociceptive stimuli by the nervous
system. Here, we propose to investigate the effects on nociceptive processing by Analgesic Screen 1 (AS1), a
small molecule we discovered that reverses the hedonic motivation (movement toward or away from) of
nociceptive stimuli including heat and the noxious chemical allyl isothiocyanate (AITC) in larval zebrafish,
rendering these highly aversive stimuli attractive or rewarding in a dose dependent manner. Remarkably, AS1
can tune the valence of nociceptive stimuli, transforming the valence from aversive to neutral to attractive. AS1
has no previously identified target or function. We hypothesize that AS1 potentiates the activity of the
dopamine reward system via D1 receptor activation by promoting release of dopamine in the presence of
nociceptive stimuli. Experiments in this proposal will make use of the unique advantages of the zebrafish and
mouse model systems to test these hypotheses and when completed, we will have characterized the effects of
AS1 on nociception and identified upon which neural circuits AS1 acts to invert the valence of nociceptive
stimuli from aversive to attractive. In Aim 1, we propose to determine the effects of AS1 on aversion evoked by
nociceptive and other aversive stimuli and how these stimuli alter neuronal activity in the CNS in the presence
or absence of AS1 in zebrafish. In Aim 2, we will use a comprehensive genetic approach to assess the role of
D1 receptor dependent dopaminergic signaling on aversion elicited by nociceptive stimuli in the presence or
absence of AS1 in zebrafish. In Aim 3, we will ascertain the effect of AS1 on nociception, place aversion,
whether these effects are dependent on D1 receptor activation and where AS1 effects neuronal activity in the
CNS in response to nociceptive stimuli using the mouse model system.