Antinociception induced by systemic administration of local anaesthetics depends on a central cholinergic mechanism

Abstract

The antinociceptive effects of systemically‐administered procaine, lignocaine and bupivacaine were examined in mice and rats by using the hot‐plate, writhing and tail flick tests. In both species all three local anaesthetics produced significant antinociception which was prevented by atropine (5 mg kg−1, i.p.) and by hemicholinium‐3 (1 μg per mouse, i.c.v.), but not by naloxone (3 mg kg−1, i.p.), α‐methyl‐p‐tyrosine (100 mg kg−1, s.c.), reserpine (2 mg kg−1, i.p.) or atropine methylbromide (5.5 mg kg−1, i.p.). Atropine (5 mg kg−1, i.p.) which totally antagonized oxotremorine (40 μg kg−1, s.c.) antinociception did not modify morphine (5 mg kg−1, s.c.) or baclofen (4 mg kg−1, s.c.) antinociception. On the other hand, hemicholinium, which antagonized local anaesthetic antinociception, did not prevent oxotremorine, morphine or baclofen antinociception. Intracerebroventricular injection in mice of procaine (200 μg), lignocaine (150 μg) and bupivacaine (25 μg), doses which were largely ineffective by parenteral routes, induced an antinociception whose intensity equalled that obtainable subcutaneously. Moreover, the i.c.v. injection of antinociceptive doses did not impair performance on the rota‐rod test. Concentrations below 10−10 m of procaine, lignocaine and bupivacaine did not evoke any response on the isolated longitudinal muscle strip of guinea‐pig ileum, or modify acetylcholine (ACh)‐induced contractions. On the other hand, they always increased electrically‐evoked twitches. The same concentrations of local anaesthetics which induced antinociception did not inhibit acetylcholinesterase (AChE) in vitro. On the basis of the above findings and the existing literature, a facilitation of cholinergic transmission by the local anaesthetics is postulated; this could be due to blockade of presynaptic muscarinic receptors.

Caffeine induces central cholinergic analgesia

“…A presynaptic mechanism facilitating cholinergic transmission is involved in caffeine antinociception as revealed by HC-3 antagonism. A postsynaptic mechanism of action can be ruled out since, as reported by Bartolini et al (1987;, HC-3 was not able to antagonise antinociception induced by agonists of postsynaptic muscarinic receptors such as oxotremorine, McN-A-343 and AF-102B. The integrity of the central cholinergic system is, therefore, fundamental for caffeine antinociception.…”

“…The doses and administration schedules of naloxone, CGP 35348, α-methyl-p-tyrosine and reserpine were suitable for preventing antinociception induced respectively by morphine (Ghelardini et al 1990), GABA B agonist baclofen (Malcangio et al 1991), amphetamine (Bartolini et al 1987) and the antidepressant drugs clomipramine and amitriptyline (Galeotti et al 1995).…”

“…Furthermore, in the rat cerebral cortex, caffeine reduced the inhibition of ACh release produced by morphine (Jhamandas et al 1978;Phillis et al 1980). It has long been known that ACh (Pedigo et al 1975), selective M 1 agonists such as McN-A-343 and AF-102B , unselective muscarinic agonists such as tremorine (Lenke 1958), oxotremorine (George et al 1962;Bartolini et al 1987), arecoline (Herz 1962), pilocarpine (Hendershot and Forsaith 1959) and cholinesterase inhibitors such as physostigmine (Harris et al 1969;Ireson 1970) and diisopropyl phosphorofluoridate (Lentz et al 1969) induce antinociception in laboratory animals by the activation of the cholinergic system. Moreover, the amplification of cholinergic neurotransmission induced by antagonism of muscarinic autoreceptors Gualtieri et al 1989;Ghelardini et al 1990) or, alternatively, by interaction with heteroreceptors ) located on presynaptic cholinergic terminals, produces a central antinociceptive effect.…”

Prochlorperazine induces central antinociception mediated by the muscarinic system

“…A presynaptic mechanism facilitating cholinergic transmission is involved in prochlorperazine antinociception as revealed by the antagonism by HC-3 postsynaptic mechanism of action can be ruled out since, as reported by Bartolini et al [33,36], HC-3 was not able to antagonise antinociception induced by agonists of postsynaptic muscarinic receptors such as oxotremorine, McN-A-343 and AF-102B. The hypothesis of a presynaptic cholinergic mechanism for prochlorperazine is further supported by microdialysis studies, in which an increase in ACh release from rat cerebral cortex was induced by prochlorperazine administration.…”

5-HT1A Agonists Induce Central Cholinergic Antinociception

“…It has long been known that the direct and indirect activation of the cholinergic system produces analgesia in both animals (1,2,9,(16)(17)(18)21,23,24) and humans (20). Because sumatriptan is endowed with cholinergic antinociceptive properties and 8-OH-DPAT enhances ACh release, the goals of the present study were to explore whether other 5-HT 1A agonists, such as gepirone and 8-OH-DPAT, were able to increase the pain threshold in mice and then investigate whether a cholinergic mechanism underlies 5-HT 1A antinociception.…”