Cross-tolerance between spinal neostigmine and morphine in the rat.
BACKGROUND
Direct or indirect acting cholinergic muscarinic agonists such as neostigmine, are potent antinociceptives when administered intrathecally (i.t.). This study examines whether spinal neostigmine tolerance and cross-tolerance to spinal morphine occurs.


METHODS
Rats (32/group) were implanted with miniosmotic pumps delivering either i.t. saline 1 microl h(-1) (S), morphine 10 nmol microl(-1) h(-1) (M), or neostigmine 3 nmol microl(-1) h(-1) (N). Latencies (infrared thermal withdrawal rear paw) were measured daily for 6 days after which four animals from each group were given one i.t. challenge dose of morphine (m) 0.1, 1, 10, or 100 nmol, or neostigmine (n) 0.3, 3, 10, or 30 nmol.


RESULTS
Neostigmine and morphine-infused animals both developed tolerance to spinal neostigmine, but neostigmine-infused animals showed no significant cross-tolerance to spinal morphine; mean ED(50) nmol (CI 95%) dose-response values were Sn 2.6 (1.9-3.5), Mn 15.6 (9.9-24.6)*, Nn 18.7 (11.7-29.8)*, Sm 0.7 (0.4-1.1), Nm 1.2 (0.8-2.0), Mm 152 (50-461)* (*significance vs saline infused control group).


CONCLUSIONS
Thus, unidirectional cross-tolerance from morphine to neostigmine was evident. Previous studies suggest morphine has a cholinergic mechanism of action partially accounting for its antinociceptive effect, which may explain this observed unidirectional cross-tolerance.
Dunbar
S A
SA
Department of Anesthesiology, Tufts University School of Medicine, Baystate Medical Center, Springfield, MA 01199, USA. Stuart.Dunbar@bhs.org
Karamian
I G
IG
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004361:Drug Tolerance; D007260:Infusion Pumps; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009388:Neostigmine / Q000494:pharmacology*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects
D000701:Analgesics, Opioid; D002800:Cholinesterase Inhibitors; D009388:Neostigmine; D009020:Morphine