Local anesthetic-like inhibition of voltage-gated Na ⁺ channels by the partial μ-opioid receptor agonist buprenorphine

Background: Opioids induce analgesia mainly by inhibiting synaptic transmission via G protein-coupled opioid receptors. In addition to analgesia, buprenorphine induces a pronounced antihyperalgesia and is an effective adjuvant to local anesthetics. These properties only partially apply to other opioids, and thus targets other than opioid receptors are likely to be employed. Here we asked if buprenorphine inhibits voltage-gated Na channels. Methods: Na ⁺ currents were examined by whole cell patch clamp recordings on different recombinant Na ⁺ channel α-subunits. The effect of buprenorphine on unmyelinated mouse C-fibers was examined with the skin-nerve preparation. Data are presented as mean ± SEM. Results: Buprenorphine induced a concentration-dependent tonic (IC50 33 ± 2 μM) and use-dependent block of endogenous Na channels in ND7/23 cells. This block was state-dependent and displayed slow on and off characteristics. The effect of buprenorphine was reduced on local anesthetic insensitive Nav1.4-mutant constructs and was more pronounced on the inactivation-deficient Nav1.4-WCW mutant. Neuronal (Nav1.3, Nav1.7, and Nav1.8), cardiac (Nav1.5), and skeletal muscle (Nav1.4) α-subunits displayed small differences in tonic block, but similar degrees of use-dependent block. According to our patch clamp data, buprenorphine blocked electrically evoked action potentials in C-fiber nerve terminals. Buprenorphine was more potent than other opioids, including morphine (IC50 378 ± 20 μM), fentanyl (IC50 95 ± 5 μM), sufentanil (IC50 111 ± 6 μM), remifenatil (IC50 612 ± 17 μM), and tramadol (IC50 194 ± 9 μM). Conclusions: Buprenorphine is a potent local anesthetic and blocks voltage-gated Na channels via the local anesthetic binding site. This property is likely to be relevant when buprenorphine is used for pain treatment and for local anesthesia.