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The analgesic effect of three different opioid agonists, DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin), U-50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidynyl)cyclohexyl] benzene-aceramide methane sulphonate), and [D,Pen2-D,Pen5]-enkephalin, which act upon mu, delta and kappa opioid receptors, respectively, was compared in the presence and absence of salmon-calcitonin (s-CT). The analgesic test used was the writhing test in mice. The analgesic effect of the opioids was significantly enhanced by pretreatment of the animals with s-CT intraperitoneally (i.p.) administered. This effect was more evident for the delta and kappa-agonists. The present result suggests that the joint administration of s-CT and opioids may be a useful and interesting alternative in the treatment of painful diseases resistant to other treatments.

The effects of intraperitoneal (I.P.), intracerebroventricular (ICV) and intrathecal (IT) opiates were studied in the rat neuropathic pain model of Kim and Chung. Dose dependent reduction of allodynia was observed after I.P. and ICV morphine, but not after IT morphine, IT or ICV c[D-pen2 D-pen5]enkephalin (DPDPE) (delta agonist), or IT or ICV U50488H (kappa agonist). The effects of ICV morphine were blocked by I.P. naloxone, but not by IT methysergide, phentolamine or 8-sulfophenyltheophylline. Catalepsy (immobility) was observed after IT, ICV and IT morphine but this was not reliably associated with a reduction of allodynia. I.P. and ICV morphine may thus reduce tactile allodynia via supraspinal, but not spinal, mu opioid receptors.

In recent studies, the superfusion of the corium side of the skin with inflammatory mediators failed to produce sensitization of nociceptors to mechanical stimuli. We have studied the effects of intradermal (i.d.) and subcutaneous (s.c.) injections of prostaglandin E2 (PGE2) and bradykinin (BK) in a behavioral model of hyperalgesia. PGE2 or BK was injected into the rat hind-paw, and paw-withdrawal thresholds in response to noxious mechanical stimulation before and after the drug were compared. Subcutaneous injection of PGE2 (1-1000 ng), a hyperalgesic inflammatory mediator, did not significantly alter paw-withdrawal thresholds, under the same conditions in which i.d. injections dose-dependently lowered paw-withdrawal thresholds. Similarly, BK (1-1000 ng), another hyperalgesic mediator, given s.c. failed to significantly alter paw-withdrawal thresholds while i.d. injections dose-dependently lowered paw-withdrawal thresholds. The prostaglandin E-type, EP1 receptor antagonist SC19220 (750 ng), given s.c. prior to PGE2 (i.d.) did not significantly change PGE2-induced hyperalgesia. However, SC19220 significantly attenuated PGE2 hyperalgesia when both were injected i.d. Also, s.c. administration of the mu-opioid antagonist, DAMGO, before PGE2 did not inhibit PGE2-induced hyperalgesia as opposed to i.d. injection. These results suggest that the inability of s.c. injection of PGE2 or BK to reach its receptor site on the terminals of primary afferent nociceptors may be responsible for the ineffectiveness of these hyperalgesic mediators to sensitize cutaneous nociceptors to mechanical stimuli in the rat and underscore the importance of the site of application and site of action of hyperalgesic agents in the study of hyperalgesic mechanisms.

The possible opioid control through delta, mu and kappa receptors of the spinal release of Met-enkephalin-like material (MELM) was investigated in halothane-anaesthetized rats. The intrathecal perfusion of the delta agonist DTLET (10 microM) or the mu agonist DAGO (10 microM) resulted in a marked inhibition of MELM release, which could be prevented by the selective antagonists naltrindole and naloxone, respectively. Although the kappa agonist U 50488 H (10 microM) was inactive per se, it completely suppressed the inhibitory effect of DAGO, without affecting that of DTLET. As the selective kappa antagonist norbinaltorphimine blocked the action of U 50488 H, it can be concluded that kappa receptors modulate the mu- (but not the delta-) mediated feed back control of spinal enkephalinergic neurones.

The antinociceptive activity of two new synthetic glucoside and galactoside enkephalinamide analogues was studied. The effects produced by the new analogues were compared with those obtained with [D-Met2,Hyp5]enkephalinamide and with morphine. The analogues were injected into the fourth ventricle and intrathecally. Tail immersion and paw pressure behavioural tests were used to assess antinociception. One of the analogues studied, O1,5-[beta-D-galactopyranosyl] [D-Met2,Hyp5]enkephalinamide appears to be 57,000 times more potent than morphine.

The analgesic effect of the microinjection of low doses of methione-enkephalin (20 micrograms in 0.5 microliter) into the caudal brain stem of the unrestrained rat was investigated by means of one vocalisation test. Immediate short duration significant increases in threshold (21%) were seen from sites in the nucleus raphé magnus (NRM). Delayed effects were seen from sites immediately adjacent to this nucleus; sites more lateral produced no significant effect. These results lend further support to the postulated role of NRM in antinociception.