Alpha agonists [noradrenaline (NA) and ST-91] inhibit the release of substance P (SP) from the spinal cord and block the biting, licking, scratching syndrome produced by intrathecal SP suggesting that these agents produce analgesia by an interaction with SP systems. In this study we determined the effect of a desensitizing regimen of SP (15 micrograms X 2 at a 30-min interval) on analgesia produced by intrathecal NA in the rat tail-flick test. When NA was injected immediately after the regimen or after a 90-minute delay, NA analgesia was blocked. This blockade persisted up to 11 days after exposure to SP. Exposure to a single dose of SP (15 or 30 micrograms) also blocked NA acutely, but the long-term blockade did not last as long. An identical effect was observed with ST-91. SP (15 micrograms X 2) potentiated the analgesic action of morphine acutely, but no interaction was observed 4 to 7 days later. Pretreatment with morphine and naloxone prevented the long-term blockade by SP. The effect of naloxone was not reversed by naltrexone suggesting that occupation of opiate receptors rather than an apparent agonist effect of naloxone caused the protection. Pretreatment with clonidine had only a slight effect on long-term blockade, but yohimbine was without effect. The present study describes a new long-term interaction between SP and alpha-2 agonists in the spinal cord. The mechanism(s) of the observed blockade by SP remains to be elucidated. However, there appears to be a functionally significant interaction between opiate and alpha-2 receptors in the spinal cord.