Differential block of N-propyl derivatives of amitriptyline and doxepin for sciatic nerve block in rats.
OBJECTIVE
The propyl group of ropivacaine ( N -propyl-2',6'-pipecoloxylidide hydrochloride) could be responsible for conferring some sensory selectivity to this drug. Thus, adding a propyl group to experimental local anesthetics (LAs) (e.g., the tricyclic antidepressants amitriptyline and doxepin) to increase sensory selectivity may be useful. We, therefore, synthesized N -propyl amitriptyline and N -propyl doxepin and investigated a potential predominance of sensory/nociceptive block over motor block (differential block) in a rat sciatic nerve block model. In addition, tetrodotoxin (TTX), a naturally occuring Na + channel blocker, was coinjected to investigate whether it increased block duration.


METHODS
A 0.2-mL test dose of N -propyl amitriptyline and N -propyl doxepin, at a concentration of 1, 2.5, 5, and 10 mM, (alone or in combination with TTX at a concentration of 20 microM) was injected by the subfascial sciatic nerve approach. Motor function and sensory function (nociception) were evaluated by the force a rat's hind limb produced when pushing against a balance and the reaction to pinch, respectively.


RESULTS
N -propyl amitriptyline and N -propyl doxepin demonstrated prolonged block duration, with N -propyl amitriptyline displaying significant differential block at higher concentrations (5 and 10 mM). The combination of either of these drugs with TTX increased the potency as well as the efficacy. Neurotoxicity commenced at concentrations of 5 to 10 mM.


CONCLUSIONS
Detailed histopathologic nerve toxicity evaluations are justified to determine whether N -propyl amitriptyline has potential as a more sensory-selective local anesthetic at lower concentrations or as a predominantly sensory-selective neurolytic agent at higher concentrations.
Gerner
Peter
P
Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. pgerner@partners.org
Luo
Shi Hua
SH
Zhuang
Zhi-Ye
ZY
Djalali
Alimorad G
AG
Zizza
Anthony M
AM
Myers
Robert R
RR
Wang
Ging Kuo
GK
D000639:Amitriptyline / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004316:Doxepin / Q000031:analogs & derivatives / Q000494:pharmacology*; D005260:Female; D009407:Nerve Block; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects* / Q000473:pathology; D013779:Tetrodotoxin / Q000494:pharmacology
D004316:Doxepin; D000639:Amitriptyline; D013779:Tetrodotoxin