Morphine and other opioids are among the most effective analgesics for treating pain. However, drug dependence and other deleterious side effects of opioids have limited their clinical applicability. Recent studies suggest that the use of opioids for pain control may even exacerbate disease outcomes in some pain-producing conditions, such as acute pancreatitis [1]. Thus, there is a clinically unmet demand for the discovery of new therapeutic targets for developing a new generation of analgesics potentially devoid of opioid-like adverse side effects. In most cases, the initial proof-of-concept identification of a protein as a potential druggable target is dependent on the use of genetically modified rodent models, such as gene-knockout mice. However, knocking out the targeted gene may produce undesirable modifications of other functionally coupled genes. These off-target side effects discredit target validation work using genetic methods. For instance, Nav1.7-knockout mice or humans with a Nav1.7 loss-of-function mutation exhibited remarkably low sensitivity to pain [2,3,4,5], which led to substantial efforts by academics and the pharmaceutical industry in a search for Nav1.7-specific antagonists [2,3,4,5]. However, it turned out that potent and selective Nav1.7 antagonists have weak analgesic activity [6]. Later studies found that disrupted opioid-related signaling contributes to the low pain sensitivity in humans and mice lacking Nav1.7 [7]. Due to the intrinsic problem of the genetic methods, selective chemical probes provide a complementary means of target discovery and validation, particularly in pain.