1 The role of arachidonic acid metabolites and oxygen radicals in carrageenin-induced rat paw oedema and dermal reverse passive Arthus reaction (RPA) have been investigated. 2 Indomethacin (10 mg kg-', p.o.) inhibited carrageenin paw oedema when administered 30 min before, but not 2 h after carrageenin. BWB70C (10 mg kg-', p.o.), a selective inhibitor of 5-lipoxygenase, had no effect whether administered before or after carrageenin. Administration of both indomethacin and BWB70C had no greater anti-inflammatory effect than indomethacin alone. 3 BW755C (20 mg kg-, p.o.), which inhibits the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism, or superoxide dismutase-polyethylene glycol conjugate (SOD-PEG, 3000 u, i.v.) inhibited carrageenin paw oedema whether administered either 30 min before, or 2 h after carrageenin.4 Pretreatment with dexamethasone (0.1 mg kg-') or colchicine (2 mg kg-'), likewise suppressed carrageenin paw oedema. 5 BW755C (25-100mgkg-', p.o.) dose-dependently reduced plasma leakage in the RPA, whereas indomethacin (5mgkg-', p.o.) or BWB70C either alone or in combination, did not. 6 SOD-PEG (300-3000 u, i.v.) dose-dependently inhibited plasma leakage in the RPA. In addition, the iron chelator and peroxyl radical scavenger, desferrioxamine (200mgkg-', s.c.) also inhibited plasma leakage. 7 Pretreatment with dexamethasone (0.1 mg kg-') or colchicine (1 mg kg-l) reduced the plasma leakage in RPA, whereas MK-886 (10mgkg-1) had no effect. 8 These results indicate an important role for oxygen radicals but not arachidonic acid metabolites in the maintenance of carrageenin paw oedema and the plasma leakage in RPA. Furthermore, the results suggest that the anti-inflammatory actions of BW755C can be dissociated from its effects on arachidonic acid metabolism and are attributed to its anti-oxidant activity.

There is still a need for a new analgesic devoid of the side effects presented by opioids or non-steroidal anti-inflammatory drugs, for the treatment of some acute and chronic pain conditions. Lamotrigine (Lamictal1, 10-100 mg/kg), a new anticonvulsant, showed analgesic effects in the acute model of prostaglandin E2 (PGE2)-induced hyperalgesia when given orally before or after the subplantar injection of PGE2 in the rat. It also inhibited the development of sustained hyperalgesia induced by multiple subplantar injections of PGE2 when administered orally prior to the PGE2 injections. Furthermore, lamotrigine induced analgesia in the model of chronic hyperalgesia in streptozotocin-induced diabetic rats. The effects of carbamazepine and phenytoin are compared to the effects of lamotrigine in this model. The results suggest that lamotrigine could be used in pain conditions where neuronal sensitization may be present and possibly also where it could inhibit the development of this sensitization.

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The cytokine interleukin-lf (IL-I0) is a potent hyperalgesic agent in the rat whereas IL-la is relatively inactive (Ferreira et al., 1988). IL-1fi induced a dose-dependent increase in the sensitivity of rat paws to mechanical stimulation following intra-plantar injection but this effect was not reduced by indomethacin (1.Omgkg-1, p.o.), at a dose known to inhibit completely prostaglandin synthesis in the rat (Salmon et al., 1983). Prostaglandin (PG)E2 enhanced sensitivity to both mechanical pressure and increased temperature but IL-If enhanced only sensitivity to pressure. These observations indicate that IL-I# sensitized pressuresensitive but not temperature-sensitive sensory neurones, through a prostaglandin-independent mechanism.Hyperalgesia induced by IL-1f but not PGE2, was inhibited by the neuropeptide melanocyte-stimulating hormone (aMSH) and its analogue [Nle',

1 Two selective inhibitors of arachidonate 5-lipoxygenase, BW A4C and BW A797C, have been studied for their effects on acute inflammatory responses following oral administration to rats and mice. 2 The concentrations of the lipoxygenase product leukotriene B4 (LTB4) in 6 h inflammatory exudates, induced in rats by the subcutaneous implantation of carrageenin-soaked polyester sponges, were reduced dose-dependently by BW A4C (ED5o = 2.6 mgkg-') or BW A797C (ED50= 14.3 mg kg 1). 3 BW A4C and BW A797C had little or no effect on prostaglandin E2 (PGE2) concentrations in inflammatory exudates (ED50s > 100 mg kg-1). 4 Doses of up to 200mgkg-1 of either BW A4C or BW A797C had no effect on carrageenin-induced oedema in rat paws. 5 BW A4C and BW A797C had little or no effect on carrageenin-induced hyperalgesia in rats or phenyl-benzoquinone-induced writhing in mice.6 Yeast-induced pyrexia in rats was reduced by both BW A4C (ED50 = 32mgkg-1) and BW A797C (ED5o = 23 mg kg-1).7 The accumulation of leucocytes in sponge exudates was reduced dose-dependently by BW A4C (ED5o = 54mgkg-1) and BW A797C (ED50 = 16.7mgkg-1).8 The selective lipoxygenase inhibitors BW A4C and BW A797C do not suppress inflammatory oedema or pain although they are anti-pyretic and they do inhibit leucocyte migration. There is not, however, a close agreement between these in vivo activities and their potencies as lipoxygenase inhibitors.

The design, synthesis, and biological activity of a series of highly polar enkephalin-related pentapeptides are reported. These analogues incorporate structural features that exclude them from the central nervous system and thereby restrict their action to peripherally located receptors. Hydrophilic analogues were obtained by introduction of polar D-amino acid residues at position 2 and, in certain cases, by conversion of the N-terminal amino group of the Tyr residue to a guanidino function. The peptides were synthesized by classical solution methods. All compounds demonstrated in vitro opioid activity in the GPI and all were shown to possess antinociceptive activity in chemically induced writhing models. The analgesic effects were shown to be predominantly peripherally mediated by antagonism of antinociception with the peripheral antagonist N-methylnalorphine. Comparative data obtained in writhing and hot-plate tests were also supportive of a peripheral mode of action. Compound 13a, L-tyrosyl-D-arginylglycyl-L-4-nitrophenylalanyl-L-prolinamide (BW 443C), was identified as having a favorable pharmacological profile, indicating a high level of peripheral selectivity, and worthy of further investigation.

In conclusion, we have described a novel series of acetohydroxamic acids that are potent and selective inhibitors of arachidonate 5-lipoxygenase in vitro and in vivo. In addition, we have shown that these compounds attenuate "leukotriene-dependent" anaphylactic bronchospasm, the accumulation of inflammatory leukocytes, and the development of fever in experimental models. It now remains to be determined if these compounds have any therapeutic value in man.

1 To investigate peripherally mediated antinociceptive effects of opioids, the activity of a novel polar enkephalin analogue H-Tyr-D-Arg-Gly-Phe (4-NO2)-Pro-NH2 (BW443C) has been compared with those of classical tertiary opiates against different nociceptive stimuli in the mouse. 2 In chemically-induced writhing models BW443C, administered subcutaneously, demonstrated dose-related antinociceptive effects less potent than morphine and of a similar order to pethidine and D-propoxyphene. In assays using heat as the noxious stimulus BW443C was markedly less potent than any of the opiates tested. 3 In heat-induced assays, but not in chemically-induced writhing assays, BW443C demonstrated a 'U'-shaped dose-time response relationship. Morphine, pethidine and D-propoxyphene showed simple, approximately linear, dose-time effects in all assays. 4 When given subcutaneously, the inhibitory effects of BW443C and morphine in chemicallyinduced writhing were antagonized by naloxone given intraperitoneally. The inhibitory effects on writhing of BW443C, but not those of morphine, were also antagonized by prior intraperitoneal administration of the quaternary opioid antagonist N-methyl nalorphine. When this antagonist was administered intracerebroventricularly, the antinociceptive effects in writhing of both BW443C and morphine were antagonized. 5 It is concluded that BW443C, being only poorly able to cross the blood brain barrier, demonstrates peripherally mediated opioid antinociceptive effects in chemically-induced writhing models. In heatinduced models, that detect centrally acting opioids, BW443C is effective only at high doses and at time intervals after dosing sufficient to allow slow penetration of drug into the CNS. It is suggested that the peripheral antinociceptive actions of BW443C are mediated by inhibition of sensory neurones.