Effects of coadministration of cannabinoids and morphine on nociceptive behaviour, brain monoamines and HPA axis activity in a rat model of persistent pain
Effects of coadministration of cannabinoids and morphine on nociceptive behaviour, brain monoamines and HPA axis activity in a rat model of persistent pain
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DOI：
10.1111/j.0953-816x.2004.03177.x
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发表时间：
2004-02-01
影响因子：
3.4
通讯作者：
Chapman, V
中科院分区：
文献类型：
--
作者：
Finn, DP;Beckett, SRG;Chapman, V
Delta（9）-tetrahydrocannabinol（Delta（9）-THC）的抗伤害作用已被广泛描述;然而，其治疗潜力可能受到继发性作用的限制。我们研究了低剂量大麻素或大麻素和吗啡联合给药是否在没有副作用的情况下产生抗伤害感受。给药前（i. p.）δ（9）-THC（1或2.5 mg/kg）、大麻二酚（5 mg/kg）、吗啡（2 mg/kg）、δ（9）-THC +吗啡、δ（9）-THC +大麻二酚或溶剂对福尔马林诱发的伤害性行为的影响进行了60 min的研究。评估药物对自发活动、核心体温和梳理的影响。δ（9）-THC降低了福尔马林诱发的伤害性行为的两个阶段，增强了福尔马林诱发的皮质酮反应，并增加了下丘脑中4-羟基-3-甲氧基苯乙二醇：去甲肾上腺素的比例。单独的大麻二酚对这些指数没有影响，并且不调节Delta（9）-THC的作用。吗啡减少了福尔马林引起的伤害性行为的两个阶段。δ（9）-THC和吗啡联合给药比单独给药更大程度地减少福尔马林诱发的伤害性行为的第二阶段，并增加丘脑5-羟色胺的水平。虽然单独的Delta（9）-THC和吗啡的抗伤害感受作用在对自发活动没有影响的剂量下发生，但Delta（9）-THC和吗啡的共同施用抑制自发活动。总之，在持续性伤害感受模型中，低剂量吗啡（而非大麻二酚）与Delta（9）-THC的联合给药增加了丘脑中的抗伤害感受和5-羟色胺水平。然而，这些增强的抗伤害效应与对自发活动的次级效应增加有关。
The antinociceptive effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) have been widely described; however, its therapeutic potential may be limited by secondary effects. We investigated whether coadministration of low doses of cannabinoids or cannabinoids and morphine produced antinociception in the absence of side-effects. Effects of preadministration (i.p.) of Delta(9)-THC (1 or 2.5 mg/kg), cannabidiol (5 mg/kg), morphine (2 mg/kg), Delta(9)-THC + morphine, Delta(9)-THC + cannabidiol or vehicle on formalin-evoked nociceptive behaviour were studied over 60 min. Trunk blood and brains were collected 60 min after formalin injection and assayed for corticosterone and tissue levels of monoamines and metabolites, respectively. Drug effects on locomotor activity core body temperature and grooming were assessed. Delta(9)-THC reduced both phases of formalin-evoked nociceptive behaviour, enhanced the formalin-evoked corticosterone response and increased the 4-hydroxy-3-methoxyphenylglycol: noradrenaline ratio in the hypothalamus. Cannabidiol alone had no effect on these indices and did not modulate the effects of Delta(9)-THC. Morphine reduced both phases of formalin-evoked nociceptive behaviour. Coadministration of Delta(9)-THC and morphine reduced the second phase of formalin-evoked nociceptive behaviour to a greater extent than either drug alone, and increased levels of thalamic 5-hydroxytryptamine. While the antinociceptive effects of Delta(9)-THC and morphine alone occurred at doses devoid of effects on locomotor activity, coadministration of Delta(9)-THC and morphine inhibited locomotor activity. In conclusion, coadministration of a low dose of morphine, but not cannabidiol, with Delta(9)-THC, increased antinociception and 5-hydroxytryptamine levels in the thalamus in a model of persistent nociception. Nevertheless, these enhanced antinociceptive effects were associated with increased secondary effects on locomotor activity.