The novel role of the spinal muscarinic receptors in pain.

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Opioid analgesics such as morphine are widely used for the treatment of moderate to severe pain. Furthermore, recent findings show that morphine does not fully suppress pain, such as the pain associated with diabetic neuropathy. It is because of these problems that the combination of medicines has become effective in clinical practice. Interestingly, recent reports have suggested that the cholinergic neurons in the spinal cord form part of the analgesia induced by morphine. It has been reported that the administration of a muscarine receptor antagonist suppresses the antinociceptive effects induced by the intraperitoneal administration of morphine. However, the involvement of the spinal cholinergic system in morphine-induced analgesic effects remains poorly understood.In this grant, therefore, was undertaken to clarify how muscarinic receptors in the spinal cord are involved in antinociceptive effects induced by morphine in thermal stimulation. Our studies demonstrated that the muscari … More nic M3 receptor is involved in formalin-induced nociception, and the M_1 receptor is involved in mechanical-induced nociception. In addition, blockade of spinal muscarinic receptors attenuates the antiallodynic response of the i.t. of clonidine in a rat model of neuropathic pain following peripheral nerve injury. These findings indicate that cholinergic neurons in the spinal cord may be important for antinociception.Furthermore, the morphine-induced antinociceptive effects was inhibited by an i.t. injection of the muscarinic antagonist atropine and the M_1 antagonist pirenzepine in a dose-dependent manner. In contrast, the M_2 antagonist methoctramine and the M_3 antagonist 4-DAMP did not inhibit the morphine-induced antinociceptive effects. Injection (i.t.) of the M1 agonist McN-A-343 resulted in close-dependent antinociceptive effects in thermal stimuli. In addition, antinociceptive effects induced by the i.t. injection of morphine were not inhibited by the M_1 antagonist. pirenzepine, although pirenzepine did inhibit the intracerebroventricular (i.c.v) injection of morphine-induced antinociceptive effects. These results suggest that the morphine-induced antinociceptive effects in thermal stimuli are regulated by the M_1 receptor in the spinal cord. Less