Modulation of peripheral Na(+) channels and neuronal firing by n-butyl-p-aminobenzoate.
n-butyl-p-aminobenzoate (BAB), a local anesthetic, is administered epidurally in cancer patients to treat pain that is poorly controlled by other drugs that have a number of adverse effects. The purpose of the study was to unravel the mechanisms underlying the apparent selective pain suppressant effect of BAB. We used the whole-cell patch-clamp technique to record Na(+) currents and action potentials (APs) in dissociated, nociceptive dorsal root ganglion (DRG) cells from rats, two types of peripheral sensory neuron Na(+) channels (Nav1.7 and Nav1.8), and the motor neuron-specific Na(+) channel (Nav1.6) expressed in HEK293 cells. BAB (1-100μM) inhibited, in a concentration-dependent manner, the depolarization evoked repetitive firing in DRG cells, the three types of Na(+) current expressed in HEK293 cells, and the TTXr Na(+) current of the DRG neurons. BAB induced a use-dependent block that caused a shift of the inactivation curve in the hyperpolarizing direction. BAB enhanced the onset of slow inactivation of Nav1.7 and Nav1.8 currents but not of Nav1.6 currents. At clinically relevant concentrations (1-100μM), BAB is thus a more potent inhibitor of peripheral TTX-sensitive TTXs, Nav1.7 and TTX-resistant NaV1.8 Na(+) channels than of motor neuron axonal Nav1.6 Na(+) channels. BAB had similar effects on the TTXr Na(+) channels of rat DRG neurons and Nav1.8 channels expressed in HEK293 cells. The observed selectivity of BAB in treating cancer pain may be due to an enhanced and selective responsiveness of Na(+) channels in nociceptive neurons to this local anesthetic.
Le Centre de recherche de l'Institut universitaire en santé mentale de Québec, Université Laval, Quebec City, QC, Canada.
Olivier
O
Thériault
Le Centre de recherche de l'Institut universitaire en santé mentale de Québec, Université Laval, Quebec City, QC, Canada.
Hugo
H
Poulin
Department of Pharmacology & Chemical Biology, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
Adrian
A
Sculptoreanu
Department of Pharmacology & Chemical Biology, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
William C
WC
de Groat
Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA.
Micheal E
ME
O'Leary
Le Centre de recherche de l'Institut universitaire en santé mentale de Québec, Université Laval, Quebec City, QC, Canada. Electronic address: mohamed.chahine@phc.ulaval.ca.
Mohamed
M
Chahine
D000200:Action Potentials; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D001566:Benzocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000187:drug effects / Q000378:metabolism; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000187:drug effects / Q000378:metabolism; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D061566:Voltage-Gated Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D000779:Anesthetics, Local; D062557:NAV1.6 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D026941:Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; C004605:butamben; D001566:Benzocaine
Butamben; Butamben (PubChem CID: 2482); Dorsal root ganglia; Na(v); Nociception; Sodium channels