1 Gabapentin (neurontin) is a novel antiepileptic agent that binds to the a 2 d subunit of voltagedependent calcium channels. The only other compound known to possess a nity for this recognition site is the (S)-(+)-enantiomer of 3-isobutylgaba. However, the corresponding (R)-(7)-enantiomer is 10 fold weaker. The present study evaluates the activity of gabapentin and the two enantiomers of 3-isobutylgaba in formalin and carrageenan-induced in¯ammatory pain models. 2 In the rat formalin test, S-(+)-3-isobutylgaba (1 ± 100 mg kg 71 ) and gabapentin (10 ± 300 mg kg 71 ) dose-dependently inhibited the late phase of the nociceptive response with respective minimum e ective doses (MED) of 10 and 30 mg kg 71 , s.c. This antihyperalgesic action of gabapentin was insensitive to naloxone (0.1 ± 10.0 mg kg 71 , s.c.). In contrast, the R-(7)-enantiomer of 3-isobutylgaba (1 ± 100 mg kg 71 ) produced a modest inhibition of the late phase at the highest dose of 100 mg kg 71 . However, none of the compounds showed any e ect during the early phase of the response. 3 The s.c. administration of either S-(+)-3-isobutylgaba (1 ± 30 mg kg 71 ) or gabapentin (10 ± 100 mg kg 71 ), after the development of peak carrageenan-induced thermal hyperalgesia, dosedependently antagonized the maintenance of this response with MED of 3 and 30 mg kg 71 , respectively. Similar administration of the two compounds also blocked maintenance of carrageenan-induced mechanical hyperalgesia with MED of 3 and 10 mg kg 71 , respectively. In contrast, R-(7)-3-isobutylgaba failed to show any e ect in the two hyperalgesia models. 4 The intrathecal administration of gabapentin dose-dependently (1 ± 100 mg/animal) blocked carrageenan-induced mechanical hyperalgesia. In contrast, administration of similar doses of gabapentin into the in¯amed paw was ine ective at blocking this response. 5 Unlike morphine, the repeated administration of gabapentin (100 mg kg 71 at start and culminating to 400 mg kg 71 ) over 6 days did not lead to the induction of tolerance to its antihyperalgesic action in the formalin test. Furthermore, the morphine tolerance did not cross generalize to gabapentin. The s.c. administration of gabapentin (10 ± 300 mg kg 71 ), R-(7) (3 ± 100 mg kg 71 ) or S-(+)-3-isobutylgaba (3 ± 100 mg kg 71 ) failed to inhibit gastrointestinal motility, as measured by the charcoal meal test in the rat. Moreover, the three compounds (1 ± 100 mg kg 71 , s.c.) did not generalize to the morphine discriminative stimulus. Gabapentin (30 ± 300 mg kg 71 ) and S-(+)-isobutylgaba (1 ± 100 mg kg 71 ) showed sedative/ ataxic properties only at the highest dose tested in the rota-rod apparatus. 6 Gabapentin (30 ± 300 mg kg 71 , s.c.) failed to show an antinociceptive action in transient pain models. It is concluded that gabapentin represents a novel class of antihyperalgesic agents.

SummaryFollicular B cell survival requires signaling from BAFFR, a receptor for BAFF and the B cell antigen receptor (BCR). This “tonic” BCR survival signal is distinct from that induced by antigen binding and may be ligand-independent. We show that inducible inactivation of the Syk tyrosine kinase, a key signal transducer from the BCR following antigen binding, resulted in the death of most follicular B cells because Syk-deficient cells were unable to survive in response to BAFF. Genetic rescue studies demonstrated that Syk transduces BAFFR survival signals via ERK and PI3 kinase. Surprisingly, BAFFR signaling directly induced phosphorylation of both Syk and the BCR-associated Igα signaling subunit, and this Syk phosphorylation required the BCR. We conclude that the BCR and Igα may be required for B cell survival because they function as adaptor proteins in a BAFFR signaling pathway leading to activation of Syk, demonstrating previously unrecognized crosstalk between the two receptors.

A single injection of streptozocin (50 mg/kg, i.p.) led to the development of static and dynamic allodynia in the rat. The two responses were detected, respectively, by application of pressure using von Frey hairs or lightly stroking the hind paw with a cotton bud. Static allodynia was present in the majority of the animals within 10 days following streptozocin. In contrast, dynamic allodynia took almost twice as long to develop and was only present in approximately 60% of rats. Morphine (1-3 mg/kg, s.c.) and amitriptyline (0.25-2.0 mg/kg, p.o.) dose-dependently blocked static allodynia. However, neither of the compounds was effective against dynamic allodynia. In contrast, gabapentin (10-100 mg/kg, p.o.) and the related compound pregabalin (3-30 mg/kg, p.o.) dose-dependently blocked both types of allodynia. However, the corresponding R-enantiomer (10-100 mg/kg, p.o.) of pregabalin, was found to be inactive. The intrathecal administration of gabapentin dose-dependently (1-100 microg/animal) blocked both static and dynamic allodynia. In contrast, administration of similar doses of gabapentin into the hind paw failed to block these responses. It is suggested that in this model of neuropathic pain dynamic allodynia is mediated by A beta-fibres and the static type involves small diameter nociceptive fibres. These data suggest that gabapentin and pregabalin possess a superior antiallodynic profile than morphine and amitriptyline, and may represent a novel class of therapeutic agents for the treatment of neuropathic pain.

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This paper describes the synthesis and physical and biological effects of introducing different substituents at the alpha-position of the tryptophan containing neurokinin-1 receptor antagonist [(R)-2-(1H-indol-3-yl)-1-methyl-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (CI 1021). The described compounds all exhibit less than 5 nM binding affinities for the human neurokinin-1 receptor and selectivity over the tachykinin NK(2) and NK(3) receptor subtypes. Application of variable temperature nuclear magnetic resonance spectroscopy studies of the amide and urethane protons was utilized to determine the existence of an intramolecular hydrogen bond. This intramolecular hydrogen bond increases the apparent lipophilicity to allow increased central nervous system penetration and pharmacological activity (gerbil foot tap test) in the case of the highest affinity compound [(S)-1-dimethylaminomethyl-2-(1H-indol-3-yl)-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (PD 174424) over those analogues that could not form an intramolecular hydrogen bond.