Touch-evoked Agitation Produced by Spinally Administered Phospholipid Emulsion and Liposomes in Rats

Abstract

Background Phospholipid-based liposomes can alter the kinetics of spinally administered agents. We have observed that spinal delivery of these preparations results in an unexpected touch-evoked agitation, a state in which light touch evokes vocalization by the rat. In the current study we characterized this agitated state induced by various liposome preparations. Methods Rats prepared with lumbar intrathecal catheters received a variety of phospholipids delivered spinally as emulsions or as liposomes. Before and after injection, the animal's hot-plate latency (52.5 degrees C surface), spontaneous mobility, and spontaneous and evoked pain behavior were assessed. Results Spinal delivery of L-alpha-phosphatidylcholine of egg yolk (L-EPC) and the phospholipase hydrolysis product (lyso-L-alpha-phosphatidylcholine [lyso-L-EPC]) produced dose-dependent touch-evoked agitation; the order of potency and rapidity of onset was lyso-L-EPC > L-EPC, with no difference in activity whether administered as an emulsion or as a liposome preparation. Examination of the activity of a series of pure phospholipids revealed the ordering of touch-evoked agitation potency (where PC = phosphatidylcholine) to be L-monopalmitoyl-PC (lyso product of L-dipalmitoyl-PC) > L-dipalmitoyl-PC > L-distearoyl-PC, L-dioleoyl-PC > L-dilauroyl-PC > L-dimyristoyl-PC; D-dipalmitoyl-PC = 0. The effect of unsaturation on touch-evoked agitation cannot be predicted because dioleoyl-PC and dioleoyl phosphatidylglycerol produced touch-evoked agitation but dipalmitoleoyl-PC did not. Substitution of glycerol for choline as the head group had no influence on touch-evoked agitation. Spinal treatment with an inhibitor of phospholipase (mepacrine) or a cyclooxygenase (ketorolac) blocked the touch-evoked agitation of L-EPC but not that of lyso-L-EPC. Conclusions These results emphasize that certain L-isomeric phospholipids with their gel-transition temperatures near body temperature can produce prominent touch-evoked agitation after spinal delivery, an effect likely mediated by a phospholipase hydrolysis product. This touch-evoked agitation, which is consistent with neurotoxicity reported in the early literature on lysophospholipids, suggests that the choice of lipids for the formulation of liposomes intended for spinal drug delivery should be carefully considered.