Sex Differences in Sensory-selective Nerve Blockade Induced by 2′,6′-Pipecoloxylidide

Conventional local anesthetics are commonly used to provide localized pain relief.However, conventional local anesthetics commonly block motor function, which can be problematic.For example, in labor epidurals, motor blockade can hinder ambulation, increase the likelihood of instrumental vaginal delivery, and even lead to labor arrest.1,2 Intact motor function would also be beneficial after some orthopedic surgeries and in the context of prolonged administration for chronic pain.We recently reported that 2′,6′-pipecoloxylidide (structure shown in Supplemental Digital Content fig.S1A, https://links.lww.com/ALN/E300), a metabolite of bupivacaine, ropivacaine, and mepivacaine, exhibits striking sensory-selective local anesthesia; both sciatic nerve and intrathecal administration in rats produced sensory blockade with minimal motor impairment.[3][4][5] We showed in a preliminary manner that 2′,6′-pipecoloxylidide induced sensory-selective sciatic nerve block in female rats but at higher concentrations than in male rats (Supplemental Digital Content fig.S1B, https://links.lww.com/ALN/E300).Here, we performed a systematic comparison of 2′,6′-pipecoloxylidide local anesthesia in female versus male rats.Detailed nerve block protocols, including testing and analysis, are summarized in the Supplemental Digital Content (https://links.lww.com/ALN/E300).The total number of animals in this study was 168 (see Supplemental Digital Content table S1, https://links.lww.com/ALN/E300, for the number of animals in each experiment).A concentration-response curve was generated for 2′,6′-pipecoloxylidideinjected at the sciatic nerve in female rats (fig.1).Throughout, data for male rats are from our recent publication.All female rats were weight matched with male rats (all rats weighed 350 to 450 g).In both sexes, 2′,6′-pipecoloxylidide was sensory selective.However, female rats required a higher 2′,6′-pipecoloxylidide concentration (45 mM, n = 4) than male rats (22.5 mM, n = 4) to produce 100% maximum possible effect of sensory block (Supplemental Digital Content fig.S2, https://links.lww.com/ALN/E300).In both sexes, increasing 2′,6′pipecoloxylidide concentrations prolonged the duration of sensory nerve block, but higher concentrations were required in female rats for comparable durations.For example, 45