In an electrophysiological study in anaesthetized rats, the involvement of calcitonin gene-related peptide in the spinal processing of mechanosensory information from the normal and inflamed knee joint was investigated. Calcitonin gene-related peptide(8-37), a specific antagonist at calcitonin gene-related peptide 1 receptors was administered ionophoretically close to nociceptive neurons with input from the knee joint before, during, and after development of acute inflammation in the knee induced by the intra-articular injections of kaolin and carrageenan. Calcitonin gene-related peptide (8-37) selectively antagonized the effects of ionophoretically applied calcitonin gene-related peptide but not those of ionophoretically applied substance P, neurokinin A, and (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid. Before inflammation, calcitonin gene-related peptide (8-37) reduced the responses to noxious pressure applied to the knee in 22 of 23 neurons; in 14 of 22 neurons, the responses to innocuous pressure were also reduced. In eight neurons calcitonin gene-related peptide (8-37) was administered during induction and in three periods within the first 90 min of inflammation. In these neurons the developing inflammation evoked a significantly smaller increase of the responses to innocuous and noxious pressure applied to the injected knee than in 13 control neurons which were not treated by the antagonist during induction of inflammation. In 16 of 16 neurons, calcitonin gene-related peptide (8-37) reduced the responses to innocuous and noxious pressure once inflammation and hyperexcitability of the spinal cord neurons were established. These data show that calcitonin gene-related peptide is involved in the spinal processing of mechanosensory input from the normal joint. Furthermore, this peptide and its spinal receptors significantly contribute to the generation and expression of inflammation-evoked hyperexcitability of spinal cord neurons during the development of inflammation. Finally, calcitonin gene-related peptide is involved in the maintenance of inflammation-evoked hyperexcitability. By these effects calcitonin gene-related peptide receptors may significantly contribute to the neuronal basis of hyperalgesia and allodynia associated with inflammation.