Effect of local anesthetics on the structure of a lipid bilayer as a function of the membrane composition.

OLIVEIRA-COSTA, SARA D.; PORASSO, RODOLFO D.; LÓPEZ CASCALES, JOSÉ J.

Qubec

Conferencia; 13th International Conference on Organized Molecular Film; 2010

In surgery, anesthesia provides a reversible loss of consciousness, prevention of any memory of the trauma, muscle relaxation and pain relief. Local anesthetics have been used clinically for over a century, but the molecular mechanisms by which they alter specific functions of the nervous system remain unclear. Thus, the molecular theories of general anesthesia often are divided into two categories: (l) Anesthetics may bind specifically to proteins, such as sodium channels, and alter their function directly, and (2) anesthetics may alter the functions of integral membrane proteins indirectly through modification of the physical properties of the membrane, such as its fluidity or local pressure trough the lipid bilayer. Benzocaine has been one of the most broadly used local anesthetic via superficial treatment due to its low solubility in aqueous solutions. Compared with other local anesthetics, it has a low pKa, which means it is not hydrolyzed at physiological conditions, i.e. it is always present in its neutral form. Like other molecules with anesthetic properties, benzocaine is thought to follow the Meyer-Overton Law by which the anesthetic potency is directly related with its partition coefficient between water and olive oil. However, recently, the applicability of this law has been questioned due to two anomalous behaviors. Some molecules that display high partition coefficients do not exhibit anesthetic effects. As well, the anesthetic activity is affected by the type of enantiomer used as anesthesia. In this sense, to reexamine the role of lipid membranes as the target of the anesthetic activity, a computational approach was used in which the lipid bilayer composition was systematically altered, and the impact of the anesthesia on the bilayer properties was examined. Thus, we studied the thermodynamic free energy profile associated to the benzocaine insertion into lipid bilayers and the perturbation of the local pressure in the interior of the membrane, for different ratios of lipids that form the bilayer (DiPalmitoylPhosphatidylCholine (DPPC) and DiPalmitoylPhosphatidylSerine (DPPS) ). From our simulation data, it was evidenced how the presence of benzocaine in the interior of the bilayer perturbs dramatically the pressure profile through the lipid bilayer for certain PS/PC ratios. In addition, a diminution of the barrier of free energy associated to the benzocaine penetration into the membrane was obtained with the increasing of concentration of DPPS in the membrane. These results are in good accordance with the experimental correlation existing between the molecular anesthetic activity and the membrane cell compositions.