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The position of nociceptin in relation to analgesia is still unclear. From the anatomical locations of the ORL-1 receptors it was anticipated that nociceptin would cause analgesia by both spinal and supraspinal mechanisms. In the whole animal, nociceptin does provide analgesia through spinal mechanisms, as intrathecal injection in rats produced a dose-dependent reduction of a spinal nocioceptive flexor reflex, and produced behavioural antinocioception in the tail flick test. These effects were not accompanied by sedation or motor impairment, and could not be reversed by antagonists of the opioid, α2 adrenoceptor agonist or GABA-A receptors, thus suggesting that they acted through a mechanism as yet unknown (Xu et al., 1996). However in rats and mice nociceptin given by intracerebroventricular injection unexpectedly antagonized the analgesic effects of stress, opioids and electroacupuncture, thus suggesting that the supraspinal actions of the peptide were ant-analgesic. The apparent allodynia and hyperalgesia induced by the supraspinal effects of nociceptin can be blocked by another naturally occurring peptide, which has been termed nocistatin (Okuda-Ashitaka et al., 1998; Darland & Grandy, 1998). Despite the complexity of the pathways involving the modulation of pain by nociceptin, interest continues in this field. Recent work has concentrated on the production of antagonists to nociceptin, as theoretically these may provide analgesia by supraspinal mechanisms, and therefore be more suitable as analgesic drugs in the practical situation (Meunier, 1997). When compared with opioid analgesics, a major potential advantage of nociceptin-based compounds is that, to date, they have not been seen to cause behaviour suggestive of euphoria or dysphoria, and therefore have the potential to become analgesics with limited tendency for abuse.
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