Based on the structural similarity to the parent compound and reported S1R antagonist SI 1/13 [22], we hypothesized that SI 1/28 would likewise demonstrate anti-inflammatory, anti-allodynic, and anti-hyperalgesic effects in a battery of mouse models of nociception and pain [15,16,26] with reduced liabilities associated with opioids such as drug seeking, respiratory depression, and locomotor impairment or sedation [26,27,28]. Here, TMBIM4 is linked to respiratory depression.