L. Fantetti

Role of muscarinic receptor subtypes in central antinociception

1 The ability to modify the pain threshold by the two M1‐muscarinic agonists: McN‐A‐343 and AF‐102B and by the specific M2‐agonist arecaidine was examined in mice and rats by using three different noxious stimuli: chemical (writhing test), thermic (hot‐plate test) and mechanical (paw pressure test). 2 In the mouse hot‐plate test McN‐A‐343 (20–50 μg per mouse i.c.v.) and AF‐102B (1–10 mg kg−1 i.p.) produced significant antinociception which was prevented by atropine (1 μg per mouse i.c.v.) and by the two selective M1 antagonists: pirenzepine (0.01 μg per mouse i.c.v.) and dicyclomine (0.08 μg per mouse i.c.v. or 10 mg kg−1 i.p.) but not by the specific M2‐antagonist AFDX‐116 (0.1 μg per mouse i.c.v.), naloxone (1 mg kg−1 i.p.) or by the acetylcholine (ACh) depletor hemicholinium‐3 (HC‐3) (1 μg per mouse i.c.v.). McN‐A‐343 and AF‐102B were able to increase the pain threshold also in the mouse acetic acid writhing test and in rat paw pressure test. These antinociceptive effects were completely prevented by dicyclomine (0.08 μg per mouse i.c.v. or 10 mg kg−1 i.p.) but not by AFDX‐116 (0.1 μg per mouse or rat i.c.v.). 3 In contrast with the M1‐agonists, the M2‐agonist arecaidine (0.1–2 μg per mouse or rat i.c.v.) did not induce antinociception in all three analgesic tests. However, arecaidine, at the same i.c.v. doses, was able to reduce the pain threshold in the hot‐plate and paw pressure tests. 4 The site of muscarinic control of the pain threshold is localized in the CNS since drugs which do not cross the blood‐brain barrier such as McN‐A‐343, pirenzepine and arecaidine exerted their effects only if injected i.c.v. 5 On the basis of the above findings and existing literature we suggest that the postsynaptic muscarinic receptors involved in antinociception belong to the M1 subtype. Nevertheless, presynaptic autoreceptors (M2 subtype) may play a role in pain regulation since they are involved in modulation of endogenous ACh release.

Central muscarinic antinociception induced by ET‐142 and SS‐20 in rodents

The antinociceptive effects of ET‐142 (10–50 mg kg–1 sc; 10–30 μg per mouse icv) and SS‐20 (10–50 mg kg–1 sc; 5–30 μg per mouse icv) were examined in mice by using the hot‐plate and abdominal constriction tests. A similar antinociceptive profile for both compounds (20–40 mg kg–1 ip) was also observed in rats using the paw pressure test. In the antinociceptive dose‐range, ET‐142 and SS‐20 did not impair mouse gross behavior and motor coordination evaluated, respectively, by the Irwin and rotarod tests. The increase in the pain threshold produced by ET‐142 and SS‐20 was prevented by atropine, dicyclomine, pirenzepine, and hemicholinium‐3, but not by naloxone, atropine methyl bromide, and CGP 35348. In vitro experiments showed that the two investigated compounds amplified electrically evoked guinea pig ileum contractions. On the basis of the above data, it can be postulated that ET‐142 and SS‐20 exert their antinociceptive effect through a potentiation of central cholinergic transmission. Drug Dev. Res. 42:26–34, 1997.