The present study was undertaken to investigate the plasticity of calcitonin gene-related peptide (CGRP) in antinociception after morphine tolerance in rats. The hindpaw withdrawal latencies (HWLs) to both thermal and mechanical stimulation increased significantly after intracerebroventricular injection of 2.5nmol of CGRP in opioid-naive rats, indicating that CGRP produces an antinociceptive effect in the brain. Furthermore, there was an antinociceptive effect after intracerebroventricular injection of 2.5nmol of CGRP in morphine-tolerant rats. Interestingly, the antinociceptive effect induced by intracerebroventricular injection of CGRP was lower in morphine-tolerant rats than that in opioid-naive rats at the same dose. At the same time, there was downregulation of CGRP-like immunoreactivity in both lateral septal nucleus and central nucleus of amygdala tested by immunohistochemical methods, whereas no significant changes were observed in arcuate nucleus of hypothalamus and periaqueductal gray after morphine treatment in rats. The present study demonstrates plastic changes in both CGRP-induced antinociception and CGRP-like immunoreactivity in rat brain after morphine tolerance, suggesting that CGRP may play an important role in morphine tolerance.