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The Journal of Neuroscience, April 1, 2009, 29(13):4076-4088; doi:10.1523/JNEUROSCI.0356-09.2009

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Neurobiology of Disease
The Increased Trafficking of the Calcium Channel Subunit ₂-1 to Presynaptic Terminals in Neuropathic Pain Is Inhibited by the ₂ Ligand Pregabalin

Claudia S. Bauer,¹ Manuela Nieto-Rostro,¹ Wahida Rahman,¹ Alexandra Tran-Van-Minh,¹ Laurent Ferron,¹ Leon Douglas,¹ Ivan Kadurin,¹ Yorain Sri Ranjan,¹ Laura Fernandez-Alacid,² Neil S. Millar,¹ Anthony H. Dickenson,¹ Rafael Lujan,² and Annette C. Dolphin¹

¹Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom, and ²Departamento Ciencias Medicas, Universidad de Castilla-La Mancha, 02006 Albacete, Spain

Correspondence should be addressed to either Claudia S. Bauer or Annette C. Dolphin, Laboratory of Cellular and Molecular Neuroscience, Department of Neuroscience, Physiology and Pharmacology, Andrew Huxley Building, University College London, Gower Street, London WC1E 6BT, UK, Email: c.bauer{at}ucl.ac.uk or Email: a.dolphin{at}ucl.ac.uk

Neuropathic pain results from damage to the peripheral sensory nervous system, which may have a number of causes. The calcium channel subunit ₂-1 is upregulated in dorsal root ganglion (DRG) neurons in several animal models of neuropathic pain, and this is causally related to the onset of allodynia, in which a non-noxious stimulus becomes painful. The therapeutic drugs gabapentin and pregabalin (PGB), which are both ₂ ligands, have antiallodynic effects, but their mechanism of action has remained elusive. To investigate this, we used an in vivo rat model of neuropathy, unilateral lumbar spinal nerve ligation (SNL), to characterize the distribution of ₂-1 in DRG neurons, both at the light- and electron-microscopic level. We found that, on the side of the ligation, ₂-1 was increased in the endoplasmic reticulum of DRG somata, in intracellular vesicular structures within their axons, and in the plasma membrane of their presynaptic terminals in superficial layers of the dorsal horn. Chronic PGB treatment of SNL animals, at a dose that alleviated allodynia, markedly reduced the elevation of ₂-1 in the spinal cord and ascending axon tracts. In contrast, it had no effect on the upregulation of ₂-1 mRNA and protein in DRGs. In vitro, PGB reduced plasma membrane expression of ₂-1 without affecting endocytosis. We conclude that the antiallodynic effect of PGB in vivo is associated with impaired anterograde trafficking of ₂-1, resulting in its decrease in presynaptic terminals, which would reduce neurotransmitter release and spinal sensitization, an important factor in the maintenance of neuropathic pain.

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Received Jan. 22, 2009; accepted Feb. 19, 2009.

Correspondence should be addressed to either Claudia S. Bauer or Annette C. Dolphin, Laboratory of Cellular and Molecular Neuroscience, Department of Neuroscience, Physiology and Pharmacology, Andrew Huxley Building, University College London, Gower Street, London WC1E 6BT, UK, Email: c.bauer{at}ucl.ac.uk or Email: a.dolphin{at}ucl.ac.uk

This article has been cited by other articles:

				J. P. Bannister, A. Adebiyi, G. Zhao, D. Narayanan, C. M. Thomas, J. Y. Feng, and J. H. Jaggar Smooth Muscle Cell {alpha}2{delta}-1 Subunits Are Essential for Vasoregulation by CaV1.2 Channels Circ. Res., November 6, 2009; 105(10): 948 - 955. [Abstract] [Full Text] [PDF]

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