Studies of the Mechanism of Action of Gabapentin and Pregabalin

The original animal pharmacology studies of gabapentin from Goedecke (1981-1984: W Reimann, G. Bartoszyk, and others, unpublished data) included studies of anticonvulsant action in mice, rats, and monkeys and antispasticity effects in animal models with mice, rats, and anesthetized cats. Early mechanism of action work centered on electrophysiological changes in spinal reflexes (W Steinbrecher, 1982, unpublished data) and reduced monoamine neurotransmitter release from brain tissue slices in vitro (W Reimann, E. Schlicker). Also in 1984, a group of pharmacologists at Parke-Davis (P. Boxer, R. Anderson et al., Ann Arbor, MI, unpublished data) studied gabapentin in several preclinical models of spasticity in mice. Gabapentin reduced muscle rigidity and increased locomotor agility (apparently by reducing spinal polysynaptic reflexes) at dosages of 10-100mgkg-1 IP. The results with gabapentin compared favorably with other experimental treatments for spasticity (e.g., baclofen, diazepam). Slightly later, mechanism studies focused on transport of gabapentin by the system L amino acid transporter (which proved to be the main mechanism of gabapentin entry across the gut and also across the blood-brain barrier69'70). However, the lack of pharmacological activity with several system L transporter substrates that lacked high affinity for a2-S (data not shown) soon turned attention to other potential sites of action.

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