Intracerebroventricular injections of both nicotine and substance P (SP) induced antinociception in the tail-flick test in rats. The antinociceptive effect was blocked in both cases by mecamylamine and by naloxone, suggesting that central nicotinic acetylcholine receptors and endogenous opioids are implicated in the action of these drugs. A link between substance P neurones and central cholinergic systems, involving nicotinic receptors, was also suggested by the quickly developed cross-tolerance between the antinociceptive effect of substance P and nicotine. A smaller, subeffective dose of substance P was able to block, on acute administration, the antinociceptive action of nicotine, an effect not shared by the two other mammalian tachykinins, neurokinin A or neurokinin B. The results obtained in the present study appear to indicate a dual action of substance P on central nicotinic cholinoceptors.