Prevention and reversal of morphine tolerance by the analgesic neuroactive steroid alphadolone.

OBJECTIVE: Alphadolone is a neuroactive steroid that causes antinociception in rats and analgesia in humans by interaction with spinal cord GABA(A) receptors. This study investigated whether alphadolone could affect morphine tolerance. METHODS: Morphine tolerance was induced in rats with subcutaneous sustained release morphine emulsion (M-SR; 125 mg/kg/day). Tolerance was assessed by a blinded observer using tail flick latency (TFL) response to intraperitoneal (ip) injection of immediate release morphine (M-IR 6.25 mg/kg). Fifty-five rats given M-SR were divided into three groups: group A received 1.0 mL subcutaneous emulsion containing vehicle; groups B and C had emulsions injected subcutaneously at the same time as the M-SR (B-250 mg/kg alphadolone; C-alphaxalone 80 mg/kg). RESULTS: Tail flick latency responses (percentage of maximum possible effect [% MPE]) to M-IR were reduced from 89.6 +/- 2.5 pretreatment to 20.3 +/- 4.8 after M-SR treatment (mean +/- SEM; P < 0.001, one-way anova). Coadministration of alphadolone emulsion with the M-SR caused no sedation and prevented the occurrence of morphine tolerance. TFL responses to M-IR (6.25 mg/kg) given to morphine tolerant rats were 29 +/- 8% MPE whereas the TFL was 78.6 +/- 9.8% MPE when immediate release alphadolone (10 mg/kg ip) was injected at the same time as M-IR to tolerant rats (P < 0.001 one-way anova). Alphaxalone treatment caused sedation and no effects on morphine tolerance. CONCLUSIONS: We conclude that the alphadolone can prevent morphine tolerance and it also restores normal morphine antinociception in rats with established morphine tolerance. The lack of sedation suggests clinical utility in human pain states requiring morphine.

The spinal antinociceptive effects of cholinergic drugs in rats: receptor subtype specificity in different nociceptive tests.

BACKGROUND: Several studies have shown that muscarinic cholinergic agonists cause antinociception in humans and animals when given by both spinal and non-spinal parenteral routes. It is uncertain which subtype of muscarinic receptor is involved in spinally mediated antinociceptive effects caused by these drugs. The cholinergic receptor agonists McN-A-343 (M1 selective; 3.89 to 389 nmol) and carbachol (non-selective; 0.029 to 29 nmol) were used in a rat acute pain model to investigate the involvement of M1 and non-M1 subtypes in spinally mediated antinociception. The drugs were injected intrathecally and results from experiments in which drug actions were carefully confined to the spinal cord were used to construct agonist dose response curves. RESULTS: McN-A-343 frequently diffused rostrally to the brain, away from the lumbosacral site of injection. Thus, in spite of its receptor subtype selectivity, McN-A-343 is a poor probe to use in attempting to identify receptor subtypes involved in spinal cord antinociceptive systems. However, in some experiments McN-A-343 caused spinally mediated antinociception assessed by the electrical current threshold test. Antinociception assessed by the tail flick latency test with intrathecal McN-A-343 was observed and found to involve supraspinal mechanisms. Carbachol caused spinally mediated antinociception assessed by both electrical current threshold and tail flick latency. CONCLUSIONS: The results suggest that M1 receptors are involved in spinally mediated antinociception revealed by electrical current threshold; other cholinergic receptors (non-M1) are involved in thermal antinociception at the spinal cord. This contrasts with previous work on spinally mediated cholinergic antinociception. These differences are believed to be due to difficulties in restricting the action of these drugs to the spinal cord.