Central and peripheral actions of the novel κ‐opioid receptor agonist, EMD 60400

1 The pharmacological characteristics of the κ‐opioid receptor agonist, EMD 60400, have been investigated, with particular reference to its central and peripheral sites of action and its ability to influence nociception. The κ agonists ICI 197067 and ICI 204448 were tested for purposes of comparison. 2 EMD 60400 and ICI 197067 bind with high affinity (IC50 values of 2.8 and 1.5 nm, respectively) and high selectivity to κ‐opioid receptors. ICI 204448 has a lower binding affinity (IC50 13.0 nm) and selectivity for κ‐opioid receptors. 3 EMD 60400, ICI 197067, and ICI 204448 are full and potent agonists in the rabbit vas deferens in vitro assay for κ‐opioid receptors (IC50 values of 41.8, 15.7 and 15 nm, respectively). 4 Ex vivo binding experiments in mice revealed that EMD 60400 and ICI 197067 were well taken up after s.c. administration. Brain levels of EMD 60400 were lower than those of ICI 197067 at comparable doses, indicating that EMD 60400 does not penetrate into the CNS as well as ICI 197067. 5 Haloperidol‐induced DOPA accumulation in the nucleus accumbens of the rat was dose‐dependently reversed by s.c. application of EMD 60400 and ICI 197067 at doses of and above 3 and 0.3 mg kg−1, respectively. ICI 204448 had no effect on DOPA accumulation at 30 mg kg−1, s.c. 6 Prolongation of hexobarbitone‐induced sleeping time in mice and motor impairment in the rat rotarod test were observed for EMD 60400 at doses above 3 and 2.5 mg kg−1, s.c., respectively, and for ICI 197067 at doses above 0.3 and 0.25 mg kg−1, s.c., respectively. ICI 204448 was inactive in these tests at doses of 30 and 100 mg kg−1, s.c., respectively. 7 EMD 60400 applied s.c. produced dose‐dependent naloxone‐reversible antinociception in the mouse formalin test (1st and 2nd phase ID50 0.44 and 0.47 mg kg−1, respectively) and rodent writhing test (ID50 mouse 0.55 mg kg−1 and rat 0.3 mg kg−1). Furthermore, EMD 60400 was considerably more potent in the rat pressure pain test after the induction of inflammation with carrageenin than under normalgesic conditions (ID50 values 0.1 μg kg−1 and 4.0 mg kg−1, s.c., respectively). The action of EMD 60400 (50 μg kg−1, s.c.) in the hyperalgesic pressure pain test was completely antagonized by injection of the κ‐opioid antagonist, norbinaltorphimine (100 μg) into the inflamed tissue, thus demonstrating the peripheral opioid nature of this effect. 8 EMD 60400 produced dose‐dependent inhibition of neurogenic plasma extravasation elicited by antidromic electri