1. 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 alpha(2)delta subunit 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 gabapentin, that stereoselectively interacts with the alpha(2)delta subunit of VDCCs. Thus, whilst (1S, 3R)
3-methyl gabapentin binds to the alpha(2)
delta protein with high affinity (IC(50)=42 nM), 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 alpha(2)delta subunit of VDCCs. 3. (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. 4. It is concluded that these data further support the hypothesis that the alpha(2)delta subunit of VDCCs plays an important role in the maintenance of mechanical
hypersensitivity in models of
neuropathic pain.