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 mul h(-1) (S), morphine 10 nmol mul(-1) h(-1) (M), or neostigmine 3 nmol mul(-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 ED50 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). Conclusion. 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.