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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.

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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In the present study, chronic constrictive injury (CCI model) of the sciatic nerve or tight ligation of L5 and L6 spinal nerves (Chung model) produced both dynamic and static components of mechanical allodynia in rats. The two responses were detected, respectively, by lightly stroking the hind paw with cotton wool or application of pressure using von Frey hairs. Animals with spinal nerve ligation developed both types of responses at a faster rate compared to animals with the CCI. Morphine (1-3 mg/kg, s.c.) dose-dependently blocked static but not dynamic allodynia. In contrast, pregabalin (previously S-isobutylgaba and CI-1008) dose-dependently (3-30 mg/kg, p.o.) blocked both types of allodynia. In CCI animals, two administrations of capsaicin (100 microg/50 microl) into the plantar surface of the ipsilateral paw at 1-h intervals blocked the maintenance of thermal hyperalgesia without affecting either static or dynamic allodynia. The similar administration of a further two doses of capsaicin into the same animals blocked the maintenance of static allodynia without affecting the dynamic response. These data indicate that thermal hyperalgesia, static and dynamic allodynia are respectively signalled by C-, Adelta- and Abeta/capsaicin insensitive Adelta- primary sensory neurones. It is suggested that pregabalin possesses a superior antiallodynic profile than morphine and may represent a novel class of therapeutic agents for the treatment of neuropathic pain.

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The effect of neuropeptide cholecystokinin (CCK) receptor agonists and antagonists was examined in the rat elevated X-maze model of anxiety. The selective CCK-B receptor antagonists CI-988 (PD 134308) and L-365,260 produced anxiolytic-like effects, whereas MK-329, a CCK-A receptor antagonist, was respectively less potent by factors of 313 and 200. The intracerebroventricular administration of the nonselective CCK receptor agonist caerulein or the selective CCK-B receptor agonist pentagastrin increased dose dependently the level of anxiety. CI-988 dose dependently antagonized the anxiogenic response to pentagastrin but not that induced by pentylenetetrazol. These results strongly suggest that activation of the brain CCK-B receptor induces anxiety and that selective antagonists of this receptor represent a separate class of anxiolytic agents.Although originally described as a hormone in the gastrointestinal tract (1), cholecystokinin (CCK) also has been shown to be present in high concentrations in certain neurones ofthe brain (2), where it exists as the octapeptide CCK-8 in the sulfated (CCK-8S) and desulfated forms (3, 4). Receptors for CCK have been divided into two types: (i) the CCK-A receptor that is blocked selectively by L-364,718 and is found in peripheral tissues as well as discrete brain areas (6, 7), and (ii) the CCK-B receptor that is present throughout the brain (6) and is characterized by a high affinity for the novel antagonists CI-988 (PD 134308) and L-365,260 (8, 9). The CCK-B receptor is similar or identical to the peripheral gastrin receptor (9). CCK is present in high concentrations in the limbic system (10), an area involved in the control of emotion and anxiety. Furthermore, in some neurones CCK coexists with other neurotransmitters including y-aminobutyric acid (GABA) (11,12), and agents that modify GABAergic neurotransmission in the brain (13)-for example, benzodiazepines-possess anxiolytic properties (14). These observations prompted us to study the role of CCK in anxiety, and recently we reported that a CCK receptor antagonist, CI-988, produces anxiolytic effects in a number of animal models of anxiety (8). However, this study has raised several important MATERIALS AND METHODSAnimals. Male hooded Lister rats (200-250 g) were obtained from Olac (Bichester, U.K.). Animals were housed in groups offive under a 12-hr light/dark cycle (lights on at 0700) with food and water ad libitum.Implantation of Intracerebroventricular (i.c.v.) Cannulas. For i.c.v. administration, rats were anesthetized by using a mixture of diazepam (2.5 mg/kg of body weight, i.p.) and Hypnorm (0.315 mg of fentanyl citrate and 10 mg of fluanisone per ml; 0.2 ml/kg). A 22-gauge stainless-steel guide cannula was implanted unilaterally by using a Kopf stereotaxic frame [anterior-posterior = 8.2 mm anterior of interaural line; lateral = +1.4 mm; dorsoventral = 6.6 mm dorsal to the interaural line according to the atlas of Paxinos and Watson (18)]. Animals were allowed 5-7 days to recover from surgery before behav...

1 Current analgesic therapy is dominated by NSAIDs and opiates, however these agents have limited ecacy in the treatment of neuropathic pain. The novel anticonvulsant agent gabapentin (Neurontin) has been shown to be an eective treatment for neuropathic pain in the clinic. Recent studies have demonstrated that gabapentin selectively interacts with the a 2 d subunit of voltage dependent calcium channels (VDCCs) which may be important in its mechanism of action. 2 Previous studies have identi®ed a gabapentin analogue, 3-methyl gabapentin, that stereoselectively interacts with the a 2 d subunit of VDCCs. Thus, whilst (1S,3R) 3-methyl gabapentin binds to the a 2 d protein with high anity (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 a 2 d subunit of VDCCs. 3 (1S,3R) 3-methyl-gabapentin dose-dependently (10 ± 100 mg kg 71 , p.o.) blocked the maintenance of static allodynia in the rat streptozocin and Chung models of neuropathic pain with MEDs of 30 mg kg 71. This isomer also dose-dependently blocked the maintenance of dynamic allodynia in both models with respective MEDs of 30 and 100 mg kg 71 . In contrast, (1R,3R) 3-methyl gabapentin (100 mg kg 71 , 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 a 2 d subunit of VDCCs plays an important role in the maintenance of mechanical hypersensitivity in models of neuropathic pain.