| Abstract No.: | A-D1144 |
| Country: | Canada |
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| Title: | PERIPHERAL NERVE INJURY INDUCES DOR TRAFFICKING TO CELL SURFACE IN DORSAL HORN NEURONS: IMPLICATIONS FOR NOVEL PAIN TREATMENT
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| Authors/Affiliations: | 1 Sarah V. Holdridge, 1 Catherine M. Cahill;
Queen's University, Department of Pharmacology & Tocicology, Kingston, ON, Canada |
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| Content: | Objectives: Neuropathic (NP) pain is defined as pain caused by a peripheral and/or central nervous system lesion with sensory symptoms and signs and is estimated to affect more than 1.5 % of Americans. Despite its prevalence and adverse impact on functionality and quality of life, it remains a significant challenge for physicians as it is typically refractory to traditional analgesics. However, research in ours and other laboratories increasingly suggests a therapeutic role of delta opioid receptor (DOR) agonists in treating NP pain. Following induction of NP pain in rats, intrathecal administration of Deltorphin, a selective DOR agonist, dose-dependently attenuated mechanical allodynia as assessed using calibrated von Frey filaments. Furthermore, Deltorphin produced enhanced antinociception in NP rats compared to controls in two acute thermal pain paradigms. These data suggest that NP injury induced changes in the DOR function. This functional enhancement does not appear to be a result of increased DOR biosynthesis, as DOR protein did not significantly increase. It is therefore hypothesized that alternative mechanisms, such as increased cell-surface expression, may be responsible. The objective of this study was therefore to examine the changes in neuronal cell-surface expression of spinal DORs following injury to a peripheral nerve.
Materials and Methods: We examined DOR sub-cellular localization by electron microscopy immunohistochemistry using immunogold labeling in the spinal cords of NP and control rats. The number and proximity to the plasma membrane of silver-enhanced gold particles was assessed within the dorsal horn with particular attention paid to the distribution of DORs in laminae I & II, and V, as these regions are involved in the processing of painful sensory information. Cell surface expression of DORs on dorsal root ganglia neurons was assessed by visualization of internalized fluorophore-tagged DOR ligand, as an index of functional DOR recruitment. Finally, changes in DOR message evoked by nerve injury were assessed by in situ hybridization techniques.
Results: Ultrastructural data suggest a shift in DOR compartmentalization from internal to membrane-bound within spinal cord neurons. Quantification of DOR-immunopositive dendrites in the dorsal horn revealed a bilateral increase in plasma membrane-associated DORs within lamina V neurons of NP rats compared to shams. No such increase was observed in the superficial laminae.
Conclusion: The recruitment of DORs to neuronal plasma membranes with a corresponding enhancement in antinociceptive effectiveness may represent a compensatory mechanism by which neurons may sustain an inhibitory tone during chronic pain states, and in turn, indicate a viable drug target.
(Supported by CIHR, J.P. Bickell Foundation, CFI/OIT, CRC) |
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