Calcitonin gene related peptide (CGRP), one of the most abundant peptides in the spinal cord, is localized in primary afferents and released following nociceptive stimuli. Its colocalization and corelease with substance P, a well-known nociceptive neuropeptide, support the importance of CGRP in pain mechanisms. However, its distinctive function in that regard remains to be fully established. Recently, we reported that increases in CGRP-like immunostaining and decrements in specific 125I-labelled human CGRPα ([125I]hCGRPα) binding sites in the spinal cord were correlated with the development of tolerance to the spinal antinociceptive action of a μ opioid agonist, morphine. The goal of the present study was to investigate whether the development of tolerance to other classes of opioids, namely, δ and κ agonists, can also alter CGRP-like immunostaining and receptors in the rat spinal cord. The antinociceptive effects of all opioids were monitored by the tail-immersion test. Tolerance to their antinociceptive properties was induced by the infusion for 7 days of μ (morphine sulfate, 7.5 μg/h), δ ([D-Pen2,D-Pen5]enkephalin (DPDPE), 2.0 μg/h), and κ (U-50488H, 10.0 μg/h) related agonists at the spinal level (L4), using osmotic minipumps. We confirmed that rats chronically treated with morphine showed significant decreases in [125I]CGRPα binding in laminae I, II, and III of the L4 spinal cord, while CGRP-like immunostaining was increased in these same laminae. Similar effects were observed following a treatment with the δ agonist, DPDPE, while the κ agonist, U-50488H, apparently only slightly decreased [125I]CGRPα binding in lamina II. Binding in other laminae and CGRP-like immunostaining were not affected. These results suggest a specific interaction between spinal CGRP systems and the development of tolerance to the spinal antinociceptive effects of μ- and δ-related agonists.Key words: opioid tolerance, calcitonin gene related peptide, sensory neurons, immunostaining, receptor autoradiography.