Interactions between substance P and norepinephrine in the regulation of nociception in mouse spinal cord

This study examined interactions between effects of the undecapeptide substance P and norepinephrine and the alpha-adrenoceptor agonist clonidine in the mouse spinal cord. All compounds were injected into the lumbar subarachnoid space, and effects on the tail-flick reflex and the behavioural response to intrathecal substance P were evaluated. The tail-flick response latencies were markedly increased 5-20 min. after intrathecal application of norepinephrine (0.0125-0.1 microgram) or clonidine (0.0125-0.1 microgram). The actions of both intrathecal norepinephrine (0.025 microgram) and intrathecal clonidine (0.025 microgram) were significantly attenuated when substance P (5 micrograms) was given intrathecally 55 and 45 min. before the agonists. There was a significant relationship between the tail-flick response latencies and the tail skin temperature. However, the tail-flick results were not due to changes in the skin temperature. Intrathecally applied substance P (10 ng) produced a response consisting of biting of the caudal part of the body and a few hindlimb scratches. The number of bites was significantly reduced 5 min. after injection of norepinephrine (0.1 micrograms) or clonidine (0.05-0.1 microgram), but the number of scratches was unchanged. The data show that increased stimulation of spinal alpha-adrenoceptors inhibits a spinal nociceptive reflex as well as the action of substance P in the spinal cord. Substance P modulates the action of alpha-adrenoceptor agonists on the tail-flick reflex, which may tentatively be explained by downregulation of alpha-adrenoceptors by substance P.