Cross-tolerance between spinal neostigmine and morphine in the rat

Background. Direct or indirect acting cholinergic muscarinicagonists such as neostigmine, are potent antinociceptives whenadministered intrathecally (i.t.). This study examines whetherspinal neostigmine tolerance and cross-tolerance to spinal morphineoccurs. Methods. Rats (32/group) were implanted with miniosmotic pumpsdelivering either i.t. saline 1 µl h^–1 (S), morphine10 nmol µl^–1 h^–1 (M), or neostigmine 3 nmolµl^–1 h^–1 (N). Latencies (infrared thermalwithdrawal rear paw) were measured daily for 6 days after whichfour animals from each group were given one i.t. challenge doseof 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 developedtolerance to spinal neostigmine, but neostigmine-infused animalsshowed no significant cross-tolerance to spinal morphine; meanED₅₀ 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 morphineto neostigmine was evident. Previous studies suggest morphinehas a cholinergic mechanism of action partially accounting forits antinociceptive effect, which may explain this observedunidirectional cross-tolerance. Br J Anaesth 2003; 91: 427–9