Mechanisms of the analgesic effect of calcitonin on chronic pain by alteration of receptor or channel expression

The polypeptide hormone calcitonin is well known clinically for its ability to relieve osteoporotic back pain and neuropathic pain such as spinal canal stenosis, diabetic neuropathy, chemotherapy-induced neuropathy, and complex regional pain syndrome. Because the analgesic effects of calcitonin have a broad range, the underlying mechanisms of pain relief by calcitonin are largely unknown. However, recent studies using several types of chronic pain models combined with various methods have been gradually clarifying the mechanism. Here, we review the mechanisms of the analgesic action of calcitonin on ovariectomy-induced osteoporotic and neuropathic pain. The analgesic action of calcitonin may be mediated by restoration of serotonin receptors that control selective glutamate release from C-afferent fibers in ovariectomized rats and by normalization of sodium channel expression in damaged peripheral nerves. Serotonin receptors are reduced or eliminated by the relatively rapid reduction in estrogen during the postmenopausal period, and damaged nerves exhibit hyperexcitability due to abnormal expression of Na+ channel subtypes. In addition, in chemotherapy-induced peripheral neuropathy, inhibition of signals related to transient receptor potential ankyrin-1 and melastatin-8 is proposed to participate in the anti-allodynic action of calcitonin. Further, an unknown calcitonin-dependent signal appears to be present in peripheral nervous tissues and may be activated by nerve injury, resulting in regulation of the excitability of primary afferents by control of sodium channel transcription in dorsal root ganglion neurons. The calcitonin signal in normal conditions may be non-functional because no target is present, and ovariectomy or nerve injury may induce a target. Moreover, it has been reported that calcitonin reduces serotonin transporter but increases serotonin receptor expression in the thalamus in ovariectomized rats. These data suggest that calcitonin could alleviate lower back pain in patients with osteoporosis or neuropathic pain by the alteration in receptor or channel expression.