Studies on the interaction of local anaesthetic agents with the norepinephrine transporter

Intravenous regional guanethidine Bier's block (IVRGBB) is often used to treat complex regional pain syndrome type I (CRPS 1). Guanethidine is taken up via the neuronal norepinephrine transporter (NET) and displaces norepinephrine (NE) from release vesicles.;The local anaesthetic agents cocaine, tetracaine, dibucaine, procaine, bupivacaine, prilocaine and lidocaine all inhibited the uptake of [3H]NE (as a surrogate for guanethidine) into both SH-SY5Y human neuroblastoma and HEK293 cells expressing the recombinant human NET (293-hNET) with pIC50 values ranging from 6.81 (cocaine) to 2.89 (lidocaine). Of particular interest was the prilocaine with a pIC50 of 3.72 and 3.19 in SH-SY5Y and 293-hNET cells respectively. As prilocaine is estimated to reach around 1mM in IVRGBB, such values would make a reduction in guanethidine uptake likely. Local anaesthetics were also found to displace the specific NET label [3H]nixosetine in a concentration dependent manner with pKi values ranging from 5.53 (cocaine) to 2.21 (lidocaine). Values for prilocaine were 3.16 and 3.07 in SH-SY5Y and 293-hNET cells respectively. There was a positive correlation between pIC50 (uptake) and pKi (binding) suggesting a link between uptake inhibition and specific uptake site interaction. In ex vivo electrically field stimulated mouse vas deferens, prilocaine (1mM), procaine (300M) and cocaine (30M) reduced the efficacy of guanethidine block by accelerating twitch response recovery. Furthermore, the effects of prilocaine appeared to be competitive as the inhibition was partially overcome by increasing the concentration of guanethidine.;Based on the results of this thesis, I would strongly advise that until further clinical research is carried out, guanethidine and local anaesthetic agents should not be coadministered in IVRGBB.