A modified formalin test in mice was investigated. The pain response curve induced by 0.5% formalin was biphasic, having 2 peaks, from 0 to 5 min (first phase) and from 15 to 20 min (second phase). A low concentration of formalin was used, allowing the effects of weak analgesics to be detected. Centrally acting drugs such as narcotics inhibited both phases equally. Peripherally acting drugs such as aspirin, oxyphenbutazone, hydrocortisone and dexamethasone only inhibited the second phase. Aminopyrine and mefenamic acid which acted on both central and peripheral sites inhibited both phases, but the second phase was inhibited by lower doses. Thus, this method enables one to easily distinguish the site of action of analgesics. Furthermore, pain response in the first phase was inhibited by capsaicin-treated desensitization and Des-Arg9-(Leu8)-bradykinin (bradykinin inhibitor). The second phase was inhibited by compound 48/80 pretreatment, indomethacin and bradykinin inhibitor. Therefore, it is suggested that substance P and bradykinin participate in the manifestation of the first phase response, and histamine, serotonin, prostaglandin and bradykinin are involved in the second phase. These results indicate that the first and second phase responses induced by formalin have distinct characteristic properties, and it is a very useful method for examining pain, nociception and its modulation by pharmacological or other means.

In a rat phrenic nerve-hemidiaphragm preparation, calcitonin gene-related peptide (CGRP) increased the twitch contraction induced by nerve or transmural stimulation dose dependently. Either electrical or high K+ stimulation of the phrenic nerve caused release of a CGRP-like immunoreactive substance (CGRP-LIS) in a Ca2(+)-dependent manner. Electrical stimulation of the phrenic nerve also increased the cyclic AMP content in diaphragm. This increase was not observed in Ca2(+)-free medium and was blocked by antiserum against CGRP. These results indicate that excitation of the motor nerve causes release of CGRP-LIS at nerve terminals and that the released CGRP-LIS increases the cyclic AMP content of skeletal muscles and potentiates twitch contraction.

Abstract-The possible mechanism of electroacupuncture (EAc) in reference to the effects of neuropeptides on serotonergic neurons in rat spinal cord was studied. The tested drugs were administered by intrathecal injection or spinal push-pull perfusion.The results showed that baclofen, substance P (SP) and naloxone administered intrathecally could reduce the tail pressure pain threshold. The pain threshold was increased by met-enkephalin (EK) and EAc. The action of EAc was antagonized by naloxone. The release of 5-HT in the spinal cord evoked by tail pressure pain stimulation (TP) was inhibited by EK, baclofen and EAc. However, naloxone could potentiate the 5-HT release evoked by TP. EAc reversed the naloxone potentiation of TP-evoked 5-HT release.The 5-HT release evoked by exogenous SP, however, was potentiated by EK and EAc. From these results, it is suggested that the influence of EAc on 5-HT release may be due to activation of enkephalin-interneurons, which presynaptically inhibit the primary sensory neurons in the spinal cord.

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