Antinociception assay type

Activation of all three types of opioid receptors (juL, 6, and k) can produce antinociception, but there are significant differences in the effects of activating different receptor types, depending on the noxious stimulus used and the animal species (seeRefs. 103,146 for excellent reviews see particularly Table 1 of Ref 103 for a summary of supraspinal opioid receptor involvement in antinociceptive assays). Although p agonists are active against aU types of noxious stimuli, the activity of k agonists... 

Kappa Receptors. Like jx and 6 receptors, activation of k opioid receptors can produce antinociceptive effects. However, the effectiveness of k opioid agonists as antinociceptive agents varies in different types of pain (see Ref 146), and k agonists are less effective in thermal antinociceptive assays involving more intense stimuli. 

Table 1 Antinociceptive activity of L-type Ca2+ channel antagonists in specified pharmacological assays.

Chlornaltrexamine (/f-CNA, 15) another naltrexone derivative modified at C-6, is a nonequilibrium antagonist which blocks irreversibly the three major opioid receptor types (ji, k and 8). Portoghese and his collaborators have developed this compound as the first affinity labelling agent of its class [58-61]. Compound (15) has an alkylating function at C-6 (classic nitrogen mustards) able to bind covalently to opioid receptors. In the tail flick assay in mice, /f-CNA inhibited morphine-induced antinociception for 3-6... 

Lobeline also demonstrates antinociceptive effects, but these are complex (135) they are observed after intrathecal but not after subcutaneous administration. Subcutaneous administration of lobeline enhanced nicotine-induced antinociception in a dose dependent manner. Removal of one or both oxygen functions from lobeline permits retention of the analgesic potency and activity of lobeline itself (134). Moreover, removal of one or both oxygens diminishes, by at least 25 times, the affinity for nicotinic receptor(s) in rat brain homogenates. It was concluded that there is no direct relationship between neuronal nicotinic receptor (primarily type) affinity and analgesia as measured by the tail-flick assay. 

Fedotozine (Jo-1196,170), which is structurally related to the acyclic k agonists, has in vivo antinociceptive effects on duodenal pain that appear to be mediated by peripheral k opioid receptors, but the compound is inactive after central administration (544). In binding assays (in dog myenteric plexus), however, this compound exhibits similar affinity = 0.3-0.8 jM) for all three types of opioid receptors (545). Unlike other k agonists, fedotozine does not induce diuresis after either s.c. or in-tracerebroventricular (i.c.v.) administration (546). Fedotozine also fails to substitute for either U50,488 or morphine in animals trained to discriminate these drugs (547). The main effects demonstrated for fedotozine have been in the gastrointestinal tract (seeRef 548 for a detailed review of the pharmacology of fedotozine), and therefore this compound has... 

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