Pharmacologic consequences of the vascular permeability of chromaffin cell transplants in CNS pain modulatory regions

The transplantation of peripheral neural tissue into the CNS has been shown to alter blood-brain barrier (BBB) permeability to intravascularly injected proteins such as horseradish peroxidase. The pharmacological consequences of such BBB alterations following the transplantation of adrenal medullary tissue, isolated bovine chromaffin cell suspensions, or PC12 cell suspensions into the pain modulatory regions of the periaqueductal gray (PAG) or subarachnoid space of the lumbar spinal cord were studied using agents that normally do or do not readily pass the BBB. The injection of nicotine in animals with adrenal medullary or chromaffin cell transplants produces potent analgesia, most likely due to the stimulated release of opioid peptides and catecholamines from the transplanted cells. This analgesia could be blocked by nicotinic antagonist mecamylamine, which normally passes the BBB, but not by nicotinic antagonist hexamethonium, which normally does not readily pass the BBB. Furthermore, quaternary nicotinic agonists tetramethylammonium and 1,1-dimethyl-phenyl-piperazinium had no effect on pain sensitivity in animals with adrenal medullary implants. The Met-enkephalin peptide analog, d-Ala-Met-enkephalinamide, which normally does not alter pain sensitivity when injected systemically due to limited penetration to the CNS, produced analgesia in animals with adrenal medullary, bovine chromaffin cell, and PC12 cell implants in the PAG, but not in control gelfoam-implanted animals. This analgesia, as well as analgesia induced by nicotine, was completely blocked by naloxone pretreatment, but not by naloxone methobromide, a quaternary derivative of naloxone that does not normally pass the BBB. Results of this study indicate that while CNS permeability to peptides and proteins is altered by peripheral neural transplants, CNS exclusion of highly charged molecules may be intact. The vasculature of such transplants may retain some characteristics of both the in situ peripheral graft tissues and the host CNS.