Kyra Shelton

Previous studies have indicated that oxytocin (OXT) reduces body weight in high fat diet (HFD)-induced obese (DIO) rodents, nonhuman primates and obese humans through reductions in food intake and increases in energy expenditure. Findings from recent pre-clinical and clinical data indicate that the long-acting glucagon-like peptide 1-receptor (GLP-1R) agonist, semaglutide, reduces body weight, in part, through reductions of food intake. Based on these findings, we hypothesized that the combined treatment of OXT and the glucagon-like 1- receptor (GLP-1R) agonist, semaglutide, would produce an additive effect to evoke weight loss in DIO rats. To test this hypothesis, rats were fed a HFD for approximately 5 months prior to being implanted subcutaneously with a 28-day minipump that infused OXT (16 nmol/day) or vehicle (VEH; saline). Data from animals that received different doses of GLP-1 and semaglutide was analyzed over the 32-day infusion period. Daily energy intake and body weight were tracked for 32 days. Body composition was assessed immediately prior to onset of treatment and near the end of the treatment period using Quantitative Magnetic Resonance (QMR; EchoMRI 4-in-1). OXT (16 nmol/day) alone and semaglutide (3 nmol/kg) alone reduced body weight by approximately 9.9±1.1% (0.05<P<0.1) and 4.3±1.4% (P<0.05), respectively (N=6-7/group), relative to pre-infusion baseline, while GLP-1 at either dose (1 or 3 nmol/kg, SC) was ineffective (P=NS). However, the combination of OXT and semaglutide (3 nmol/kg) produced a more pronounced reduction in body weight (14.1±1.4%; P<0.05) compared with either treatment alone (N=6-7/group). These effects were associated with reduced adiposity and adipocyte size (P<0.05). Together, these findings support the hypothesis that the combination of OXT and the GLP-1R agonist, semaglutide, produces an additive effect to evoke weight loss and body adiposity in DIO rats by reducing energy intake

Pain is a multi-faceted experience, including both emotional and physical components. We discovered a remarkable small molecule labeled ‘AS1’ that reverses aversion to noxious stimuli in zebrafish, inducing attraction to lethal stimuli. Furthermore, behavioral assessment in mice suggests that AS1 can block affective pain states thought to underlie the suffering associated with pain without affecting acute pain detection. With these results in mind, several questions arose - 1) Can AS1 inhibit the affective experience of pain (the assignment of emotional value)? 2) Does AS1 impair the evolutionarily beneficial response to acute thermal stimuli? & 3) What brain areas are AS1 acting upon to provide analgesia? In order to test these questions, we utilized the conditioned place aversion assay (CPA), the hot place assay to assess acute pain, and utilized cFos expression to assess where in the brain AS1 might be acting. In the CPA assay, we used the noxious stimulus formalin to evoke place aversion. We tested whether AS1 would alter the degree of aversion displayed by the mice. Strikingly, mice displayed no preference for either side when AS1 was administered during the conditioning phase, suggesting that AS1 blocked formalin-induced aversion. The hot plate assay revealed that AS1 does not affect acute pain sensation at dosages that ablate formalin evoked pain states. These data further support the hypothesis that AS1 specifically targets emotional/affective pain while leaving acute pain detection intact. With this in mind, we examined how AS1 effects neuronal activity in the presence of noxious stimuli (formalin) in brain areas required for encoding affective pain including - the nucleus accumbens, the anterior cingulate cortex and the basolateral amygdala. Both the nucleus accumbens and anterior cingulate cortex displayed heightened activity, whereas the basolateral amygdala displayed lower activity in mice treated with AS1 and formalin when compared to controls. These data indicate that AS1 is acting on affective pain processing centers and provides a starting point to examine how AS1 is altering brain activity to suppress affective pain. AS1 could be a promising future therapeutic agent for chronic and persistent pain conditions. Further research into its impact and the mechanisms underlying its neural action will be crucial in determining the merits of AS1 for therapeutic use.