Antinociceptive effects of the novel opioid peptide BW443C compared with classical opiates; peripheral versus central actions

Abstract

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.

Evaluation of opioid‐induced antinociceptive effects in anaesthetized and conscious animals

“…Although probably a p-receptor agonist, the high doses of BW443C required to obtain antinociceptive effects in the tail-flick assay support recent findings that this opioid peptide is less potent where CNS penetration is required (Follenfant et al, 1988). U50488 also failed to increase latency in the tail-flick assay, supporting the notion that K-receptor agonists are relatively ineffective against thermallyinduced nociception (Tyers, 1980).…”

“…However, the selective p-receptor agonist DAGOL (Kosterlitz & Paterson, 1981;Handa et al, 1981) exhibited a more prolonged hypotension and the time-course of this effect may have exceeded inhibition of reflex depressor responses. Similar problems were encountered in the quantitative evaluation of the opioid peptide BW443C, a postulated p-receptor agonist that displays peripherally-mediated antinociceptive effects (Follenfant et al, 1988). In contrast to U50488, dynorphin41-13) (1 mgkg'-i.v.…”

“…Using the PBQ-induced writhing model, Follenfant et al (1988) have demonstrated antagonism of the effects of BW443C, but not morphine, by Nmethylnalorphine, a quaternary opioid antagonist which acts preferentially at p-receptor sites (Kobylecki et al, 1982;Magnan et al, 1982) and which has a limited penetration to the CNS . In the current studies, peripherally mediated effects of ligands selective for the preceptor were observed on BP, but not on the VDR.…”

The critical role of leukotriene B4 in antigen‐induced mechanical hyperalgesia in immunised rats

“…This method has been used to demonstrate the contribution of eicosanoids, sympathetic amines, cAMP and cytokines to the development of peripheral inflammatory hyperalgesia (Ferreira & Nakamura, 1979a; Ferreira et al ., 1988; 1993; Francischi et al ., 1988; Cunha et al ., 1991; 1992; 1999), as well as the peripheral analgesic effect of opiates (Ferreira & Nakamura, 1979b) and NSAIDs (Ferreira et al ., 1988; Cunha et al ., 1991; 1992). These concepts and findings have been extensively confirmed with other methodologies such as formalin‐induced flinching (Vinegar et al ., 1976; Choi et al ., 2001; Granados‐Soto et al ., 2001), chemically induced writhing (Duarte et al ., 1988; Follenfant et al ., 1988; Ribeiro et al ., 2000b), the classical Randall‐Sellito method (Aley et al ., 1995) and others (Vinegar et al ., 1976; Safieh‐Garabedian et al ., 2002). Furthermore, this method is able to discriminate between peripheral and central analgesic effects of drugs (Ferreira et al ., 1978; Duarte & Ferreira, 1992).…”

Teleantagonism: A pharmacodynamic property of the primary nociceptive neuron

“…Typically, the reaction time before treatment was 31.5 Ϯ 1 s (mean Ϯ SEM; n ϭ 5). This method has been used extensively in our previous studies over the years, where the results have been replicated by other laboratories and by us, using the same or other nociceptive behavioral tests (11,40,41). To choose the single dose used for the agonists, receptor antagonists, and enzyme inhibitors, these agents were previously tested in pilot dose-response studies performed before the experiments described.…”