[3H] pregabalin binding is increased in ipsilateral dorsal horn following chronic constriction injury.
Pregabalin, a 3-substituted analogue of gamma-amino butyric acid has recently been approved for treatment of neuropathic pain. We have investigated the anatomical binding profile of [(3)H] pregabalin following chronic constriction injury (CCI) and compared this with alpha 2 delta 1 subunit expression using in situ hybridisation. We report here that the intensity and distribution pattern of [(3)H] pregabalin binding is altered in the ipsilateral dorsal horn following CCI and this is associated with a corresponding increase in alpha 2 delta 1 mRNA in the ipsilateral dorsal root ganglion (DRG). It is likely that increased DRG mRNA production leads to increased alpha 2 delta 1 protein production and subsequent transport by primary afferents to the dorsal horn. The increased expression of calcium channel subunits and protein in central terminals is interesting, given that abnormal activity within sensory nerves is likely to significantly contribute to the symptomatology of neuropathic pain. The upregulation of pregabalin binding sites in sensory nerve terminals may occur as part of the response to nerve damage in neuropathic pain patients, and therefore, preferential actions of pregabalin at these sites may contribute to its mechanism of action in man.
Melrose
Heather L
HL
Pain Therapeutics, Discovery Biology, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
Kinloch
Ross A
RA
Cox
Peter J
PJ
Field
Mark J
MJ
Collins
David
D
Williams
Dic
D
D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism; D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics; D020746:Calcium Channels, L-Type; D002908:Chronic Disease / Q000628:therapy; D003714:Denervation; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D008026:Ligation / Q000009:adverse effects; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism; D000069583:Pregabalin; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D000700:Analgesics; C486060:Cacna2d1 protein, rat; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D009479:Neuropeptides; D012333:RNA, Messenger; D014316:Tritium; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid