M. Naguib et Tl. Yaksh, CHARACTERIZATION OF MUSCARINIC RECEPTOR SUBTYPES THAT MEDIATE ANTINOCICEPTION IN THE RAT SPINAL-CORD, Anesthesia and analgesia, 85(4), 1997, pp. 847-853
Spinal cholinergic receptors are involved in mediating antinociceptive
effects. To characterize the receptor subtypes modulating nociceptive
transmission, we first determined the antinociceptive effects of intr
athecally administered muscarinic agonists (McN-A-343 and carbachol) a
nd a cholinesterase inhibitor (neostigmine) in rats. The antagonist po
tencies of muscarinic antagonists with different preferences for musca
rinic receptors [atropine, pirenzepine (M-1), methoctramine (M-2), and
4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; M-3)] were t
hen examined for McN-A-343, carbachol, and neostigmine. After determin
ing the time of peak effect for each antagonist, the just maximally ef
fective (JME) dose of each agonist was given in conjunction with one o
f the several doses of the antagonists. The three agents produced a do
se-dependent increase in paw withdrawal latency, with the following 50
% effective dose and the following JME doses: neostigmine 6 and 14 nmo
l, carbachol 29 and 110 nmol, and McN-A-343 354 and 630 nmol. The rank
of order of potency (and median infective dose in nanomoles) for the
antagonists was: neostigmine = (atropine 14 > 4-DAMP 44 >> methoctrami
ne > 137, and pirenzepine > 236); carbachol = (pirenzepine 0.5 = atrop
ine 0.6 > 4-DAMP 5 >> methoctramine > 137); McN-A-343 = (pirenzepine 0
.5 > atropine 3 > 4-DAMP 6 >> methoctramine > 137). Our results sugges
t that the M-1 and possibly the M-3 muscarinic receptors mediate spina
l antinociception in the rat. Implications: Spinal muscarinic agonists
, such as carbachol and the cholinesterase inhibitor neostigmine, indu
ce a potent analgesia in the rat. Using selective receptor antagonists
, we have shown that these effects are likely mediated by spinal M-1 a
nd/or M-3 receptor subtypes.