Further evidence for the role of the alpha(2)delta subunit of voltage dependent calcium channels in models of neuropathic pain

1 Current analgesic therapy is dominated by NSAIDs and opiates, however the se agents have limited efficacy in the treatment of neuropathic pain. The n ovel anticonvulsant agent gabapentin (Neurontin) has been shown to be an ef fective treatment for neuropathic pain in the clinic. Recent studies have d emonstrated that gabapentin selectively interacts with the alpha(2)delta su bunit of voltage dependent calcium channels (VDCCs) which may be important in its mechanism of action, 2 Previous studies have identified a gabapentin analogue, 3-methyl gabapent in, that stereoselectively interacts with the alpha(2)delta subunit of VDCC s. Thus, whilst (1S,3R) 3-methyl gabapentin binds to the alpha(2)delta prot ein with high affinity IC50=42 nM), the corresponding (1R,3R) isomer is 300 times weaker (Bryans et al., 1998: J. Med. Chem., 41., 1838-1845). The pre sent study examines the activity of diastereoisomers of 3-methyl gabapentin in two rat models of neuropathic pain to assess the importance of an inter action with the alpha(2)delta subunit of VDCCs. 3 (1S,3R) 3-methyl-gahapentin dose-dependently (10-100 mg kg(-1), p.o.) blo cked the maintenance of static allodynia in the rat streptozocin and Chung models of neuropathic pain with MEDs of 30 mg kg(-1). This isomer also dose -dependently blocked the maintenance of dynamic allodynia in both models wi th respective MEDs of 30 and 100 mg kg(-1). In contrast, (1R,3R) 3-methyl g abapentin (100 mg kg(-1), p.o.) failed to block either static or dynamic al lodynia in the streptozocin model. 4 It is concluded that these data further support the hypothesis that the a lpha(2)delta subunit of VDCCs plays an important role in the maintenance of mechanical hypersensitivity in models of neuropathic pain.