Further evidence for the role of the α 2 δ subunit of voltage dependent calcium channels in models of neuropathic pain

Current analgesic therapy is dominated by NSAIDs and opiates, however these agents have limited efficacy in the treatment of neuropathic pain. The novel anticonvulsant agent gabapentin (Neurontin) has been shown to be an effective treatment for neuropathic pain in the clinic. Recent studies have demonstrated that gabapentin selectively interacts with the α 2 δ subunit of voltage dependent calcium channels (VDCCs) which may be important in its mechanism of action. Previous studies have identified a gabapentin analogue, 3‐methyl gabapentin, that stereoselectively interacts with the α 2 δ subunit of VDCCs. Thus, whilst (1S,3R) 3‐methyl gabapentin binds to the α 2 δ protein with high affinity (IC 50 =42 n M ), the corresponding (1R,3R) isomer is 300 times weaker ( Bryans et al ., 1998 : J. Med. Chem ., 41 , 1838–1845). The present study examines the activity of diastereoisomers of 3‐methyl gabapentin in two rat models of neuropathic pain to assess the importance of an interaction with the α 2 δ subunit of VDCCs. (1S,3R) 3‐methyl‐gabapentin dose‐dependently (10–100 mg kg −1 , p.o.) blocked 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 with respective MEDs of 30 and 100 mg kg −1 . In contrast, (1R,3R) 3‐methyl gabapentin (100 mg kg −1 , p.o.) failed to block either static or dynamic allodynia in the streptozocin model. It is concluded that these data further support the hypothesis that the α 2 δ subunit of VDCCs plays an important role in the maintenance of mechanical hypersensitivity in models of neuropathic pain.British Journal of Pharmacology (2000) 131 , 282–286; doi: 10.1038/sj.bjp.0703604