Postoperative analgesia induced by intrathecal neostigmine or bethanechol in rats

1. Cholinergic agonists and acetylcholinesterase inhibitors, such as neostigmine, produce a muscarinic receptor-mediated antinociception in several animal species that depends on activation of spinal cholinergic neurons. However, neostigmine causes antinociception in sheep only in the early, and not late, postoperative period. 2. In the present study, a model of postoperative pain was used to determine the antinociceptive effects of bethanechol (a muscarinic agonist) and neostigmine administered intrathecally 2, 24 or 48 h after a plantar incision in a rat hind paw. Changes in the threshold to punctate mechanical stimuli were evaluated using an automated electronic von Frey apparatus. 3. Mechanical hyperalgesia was obtained following plantar incision, the effect being stronger during the immediate (2 h) than the late post-surgical period. Bethanechol (15-90 microg/5 microL) or neostigmine (1-3 microg/5 microL) reduced incision-induced mechanical hyperalgesia, the effects of both drugs being more intense during the immediate (2 h) than the late post-surgical period. 4. The ED(50) for bethanechol injected at 2, 24 and 48 h was 5.6, 51.9 and 82.5 microg/5 microL, respectively. The corresponding ED(50) for neostigmine was 1.62, 3.02 and 3.8 microg/5 microL, respectively. 5. The decline in the antinociceptive potency of neostigmine with postoperative time is interpreted as resulting from a reduction in pain-induced activation of acetylcholine-releasing descending pathways. However, the similar behaviour of bethanechol in the same model points to an additional mechanism involving intrinsic changes in spinal muscarinic receptors.