Cholinergic
mediated yawning and analgesia in rats:
differential effects of muscarinic agonists and
antagonists
Gower AJ
Merrell Dow Research
Institute, 16 rue d'Ankara, 67084 Strasbourg
Cedex, France.
The existance of muscarinic receptor
subtypes in the CNS is now well accepted.
Support for this comes mainly from binding
studies and depends heavily on the selectivity
of the muscarinic antagonist, pirenzepine (Hoss
& Ellis, 1985). However, it is important to
know whether these receptor subtypes have
functional correlates. We investigated a) the
ability of cholinergic agonists to elicit 2
centrally mediated responses, yawning
(Urba-Holmgren et al. 1977) and analgesia
(Karczmar & Dun, 1978) and b) the ability of
cholinergic antagonists to inhibit these
behaviors elicited by physostigmine, 0.1 mg/kg
subcutaneously (s.c.).
Experiments were carried out between
9.00-13.30h using male Sprague-Dawley rats
(250-320g). Induction of yawning was assessed by
counting the number of yawns elicited in a 30
min period immediately following s.c. injection
of the agonists. Effects of antagonists were
assessed by injecting them 30 min prior to
physostigmine and counting the yawns elicited
during 30 min after physostigmine. ED50 values
for inhibition of yawning were calculated.
Analgesia was measured, using an Appelex DS 20
Tail-Flick apparatus, in terms of the tail flick
response to a focussed heat stimulus. Effects of
agonists were determined 20 min after s.c.
injection. Effects of antagonists were
determined by injecting them s.c. 30 min before
physostigmine and measuring the tail-flick
response 20 min after physostigmine. ED50 values
for inhibition of analgesia were calculated. In
view of poor penetration of pirenzepine into the
brain, the effects of pirenzepine and atropine
were also determined following injection into
the lateral ventricle (i.c.v.).
Yawning was induced by physostigmine
(0.025-0.4 mg/kg); RS86 (0.05-2.5 mg/kg) and
pilocarpine (0.5-4.0 mg/kg) but not by
oxotremorine (0.001-0.3 mg/kg) nor arecoline
(0.5-2.0 mg/kg). In contrast all 5 agonists
produced analgesia over these dose-ranges.
Neostigmine (0.05-0.2 mg/kg), bethanecol (0.1-10
mg/kg) and McN-A-343 (5-20 mg/kg) were inactive
or marginally active in both tests. Clear
differences were obtained in the potencies of
drugs inhibiting yawning (Y) and analgesia (A),
(ED50 values in the table); in particular
pirenzepine i.c.v. inhibited yawning but not
analgesia.
These results show that it is possible to
differentiate muscarinic receptors on the basis
of behavioural responses. Yawning was
pirenzepine-sensitive and
oxotremorine-insensitive whereas the opposite
was found for analgesia.
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