Axoplasmic transport and transepidermal iontophoresis : factors in neurogenic pain management

MacFarlane, Brett (2006). Axoplasmic transport and transepidermal iontophoresis : factors in neurogenic pain management PhD Thesis, School of Medicine, The University of Queensland. doi:10.14264/uql.2017.412

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Author MacFarlane, Brett
Thesis Title Axoplasmic transport and transepidermal iontophoresis : factors in neurogenic pain management
School, Centre or Institute School of Medicine
Institution The University of Queensland
DOI 10.14264/uql.2017.412
Publication date 2006-12-12
Thesis type PhD Thesis
Open Access Status Not Open Access
Supervisor Michael Roberts
Sheree Cross
Total pages 1v.
Language eng
Subjects 1109 Neurosciences
Formatted abstract
Application of the method of electrically facilitated ion transport across biological membranes (iontophoresis) has been successful in the treatment of neurogenic pain states (Csillik et al, 1982). Such pain states include post-herpetic neuralgia, painful diabetic neuropathy, chronic regional pain syndromes and phantom pain. The main agents used in these studies are the vinca alkaloids including vincristine and vinblastine. It has been suggested that the vinca alkaloids cause remittance of neurogenic pain via blockade of microtubules in the neuron. Microtubules are involved with the movement of important chemical transmitters within the neuron such as nerve growth factor, which has been implicated in the development and maintenance of neurogenic pain. The method used by Csillik et al (1982), in the iontophoretic delivery of vinca alkaloids was not theoretically optimal. It was therefore desirable to gain an understanding of vinca alkaloid iontophoresis in order to further understand the mechanism of action of pain relief. Considering vinca alkaloids have considerable molecular weights (approximately 850 Da) and that molecular weight is considered a factor in achieving appreciable transepidermal iontophoretic flux, the possibility of developing a predictive algorithm for flux based on molecular weight was investigated. 

An investigation into the causative aspect of neurogenic pain symptoms in the animal model described by Bennett and Xie (1988) was undertaken. In vitro and in vivo transdermal penetration studies utilizing various methods of iontophoresis were undertaken. An optimal method was determined. This method was applied to the chronic constriction injury rat pain model in a controlled manner in order to quantify the outcome. In vivo permeation studies involving iontophoresis of a group of compounds with a broad molecular weight range was undertaken. This data was pooled with literature data in an attempt to mathematically describe the effect of molecular weight on the iontophoretic permeability co- efficient.

Investigation of axoplasmic transport in the Bennett and Xie (1988) model of neurogenic pain indicated an increase in the amount of material being transported along the nerve in the retrograde direction. In vitro studies determined that the optimum conditions for vincristine iontophoresis may include a donor vehicle of HEPES buffer of approximate pH 6.2.

In vitro and in vivo studies indicated that iontophoresis of vincristine resulted in appreciable levels in the nerve without significant systemic distribution. Neuronal levels were sufficient to inhibit axoplasmic transport. When applied to the pain model, the method did not affect pain scores. Analysis of in vitro iontophoretic flux data pooled with literature data indicated that molecules of molecular weight between 500 and 6000 Da had similar fluxes. The logarithm of the iontophoretic permeability co-efficient of permeants between atomic weight 22 Da and molecular weight 500 Da, demonstrated an exponential decay profile. 

Results indicated that vincristine iontophoresis was not likely to have caused the positive effect on pain scores reported by Csillik et al (1982). Data also indicated that manipulation of the donor vehicle could positively effect the transepidermal iontophoretic penetration of vincristine compared to the method used by Csillik et al (1982). Increased vincristine flux did not result in reduction of pain scores in the Bennett and Xie (1988) model of neurogenic pain. There was however, an appreciable increase in material being transported retrogradely in nervous tissue of the affected paw in the rat. 

Where maximal drug fluxes are desirable, ideal drug candidates for transepidermal iontophoresis would have atomic/molecular weights less than 500 Da. However, for permeants of molecular weight greater than approximately 500 Da, the size of skin pores may be the predominating factor. 
Keyword Axonal transport
Pain -- Treatment

Document type: Thesis
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