Cannabinoids have been widely reported to produce antinociception in models such as tail flick and hot plate. However, their role in modulating thermal hyperalgesia is unknown. The potency of some drugs, such as the opioids, increases during hyperalgesia. Thus, we evaluated whether there is a change in the effectiveness of intrathecal cannabinoids with hyperalgesia. Additionally, we evaluated whether cannabinoids could inhibit capsaicin-evoked neurosecretion from isolated rat spinal cord. Our results indicate that 1 fmol anandamide (i.t.) completely blocked carrageenan-induced thermal hyperalgesia. However, anandamide at doses as high as 100 pmol had no effect on thermal latencies in normal animals. Additionally, anandamide inhibited K+- as well as capsaicin-evoked immunoreactive calcitonin gene-related peptide release. Finally, cannabinoid receptors were identified in sensory neurons. Collectively, these results indicate that there is an increased effectiveness of modulation of thermal nociceptive thresholds by spinal cannabinoids during hyperalgesia. This antihyperalgesic effect may be the result of cannabinoid-induced inhibition of neurosecretion from certain primary afferent fibers.