1 Nociceptive thresholds to noxious mechanical (paw pressure) and thermal (tail flick) stimuli were recorded in conscious rats. The effects of three selective K-opioid receptor agonists on the responses to these stimuli were determined following intravenous, intracerebroventricular or intrathecal administration. Results were compared with those obtained with morphine. 2 Following intravenous administration PD1 17302, U50488, U69593 and morphine produced steep parallel dose-response curves indicating antinociceptive activity when evaluated in the paw pressure test. When U50488 and U69593 were tested at a single dose of 3.3 mgkg' no effect was seen in the tail flick test. 3 When given by the intrathecal route only morphine was effective at increasing the nociceptive threshold. PD1 17302, U50488 and U69593 were without effect in either the paw pressure or tail flick tests when tested at doses up to 100lpg per rat. PD117302 caused flaccid paralysis of the hindlimbs following intrathecal administration at the top dose tested. This effect was not reversible by naloxone. 4 All three K-Opioid receptor agonists produced naloxone-reversible antinociception in the paw pressure test, and to a lesser extent in the tail flick test, when injected directly into the third cerebral ventricle with the maximum effect occurring between 5 and 10 min after administration and declining back to control levels by 60min. Morphine had a much slower onset of action with the peak effect being observed 30 min after dosing. 5 It is concluded that, under our experimental conditions in the rat, the antinociceptive effects of K-agonists are likely to be operated via an action at a supraspinal rather than a spinal site.

(DPDPE) labelled 6-sites (Ki = 1.O4pM). CI-977 also bound with negligible affinity to [3H]-(+ )3-(1-propyl-3-piperidinyl)phenol (3-PPP) labelled a-sites (Ki = 1.9jUM) and C3H]-141-[2-thienyl]cyclohexyl)piperidine (TCP) labelled PCP sites (Ki > 10pM).3 CI-977 produced a potent inhibition of the electrically-evoked contractions of the guinea-pig ileum and rabbit vas deferens with IC5o values of 0.087nm and 3.3nm, respectively. The pK5 values for the opioid antagonists naloxone (7.6) and norbinaltorphimine (10.5) supported the K nature of the CI-977-mediated effects in the smooth muscle assays. 4 CI-977 was a potent antinociceptive agent against a mechanical noxious stimulus in rats following intravenous, intramuscular, subcutaneous and oral administration. CI-977 was also effective against mechanical and chemical noxious stimuli in the mouse but ineffective against a thermal stimulus. The antinociceptive effects produced by CI-977 were completely reversed by naloxone (1 mg kg-1, s.c.). 5 At doses close to those required to produce antinociception, CI-977 also caused a naloxone-reversible diuresis and inhibition of locomotor activity. 6 The in vitro and in vivo pharmacological profile of CI-977 demonstrates that it is a potent and selective agonist at the K-opioid receptor.

To determine the role of endogenous cholecystokinin (CCK) in the regulation of food intake, the effects of the potent CCK receptor antagonist L364,718 were investigated on the intake of a palatable diet in non‐deprived rats. The effect of a single dose of proglumide was also investigated for comparative purposes. In addition, the ability of L364,718 to antagonize the reduction in food intake produced by exogenous cholecystokinin‐octapeptide (CCK8) or bombesin in food‐deprived rats was determined. L364,718 (10–100 μg kg−1, i.p.) increased the intake of palatable diet during the 30 min test period. Proglumide (300 mg kg−1, i.p.) also increased the intake of palatable diet. Conversely, CCK8 (0.5–5 μg kg−1, i.p.) produced a reduction in the intake of the diet. In fasted rats, L364,718 (100 μg kg−1, i.p.) antagonized the reduction in food intake produced by CCK8 (10 μg kg−1, i.p.) but not that produced by bombesin (50 μg kg−1, i.p.). L364,718 did not increase food intake in these animals when measured over a 6 h period. It is concluded that L364,718 is a potent, selective antagonist of the effects of CCK8 on food intake. The observation that L364,718 and proglumide increase the intake of a palatable diet provides some evidence that endogenous CCK is involved in the control of food intake in this model.

PD 117302, a new nonpeptide opioid compound shown in in vitro studies to be a selective κ‐opioid agonist, has been evaluted in vivo for antinociceptive activity and other effects characteristic of κ‐receptor activation. Dose‐related long lasting antinociception was produced by PD 117302 against a mechanical noxious stimulus in rats following intravenous, subcutaneous or oral administration. PD 117302 was effective in raising the nociceptive threshold to mechanical and chemical but not to thermal noxious stimuli in the mouse. This effect was attenuated in animals pretreated with the opioid antagonist naloxone. In addition to producing antinociception, PD 117302 also caused naloxone‐reversible locomotor impairment and diuresis, effects that are typical of κ‐agonists. PD 117302 did not cause respiratory depression, inhibition of gastrointestinal motility or naloxone‐precipated withdrawal jumping in mice, effects that are associated with actions at the μ‐opioid receptor. The pharmacological profile of PD 117302 in vivo is consistent with in vitro data suggesting that PD 117302 is a selective agonist at the κ‐opioid receptor.

The present study attempts to determine whether the novel anti‐migraine drug sumatriptan has antinociceptive activity in rodents. Sumatriptan had little or no antinociceptive activity against a range of noxious stimuli and we therefore conclude that it is unlikely that the beneficial effects of the drug in treating migraine are due to a non‐specific analgesic action.