Abstract
We have investigated whether the stress response mediated by the adrenal medulla in rats subjected to chronic constriction injury of the sciatic nerve (CCI) modulates their nocifensive behavior. Treatment with SK29661 (300 mg/kg; intraperitoneal (I.P.)), a selective inhibitor of phenylethanolamine N-methyltransferase (PNMT) that converts noradrenaline (NA) into adrenaline (A), fully reverted mechanical allodynia in the injured hind paw without affecting mechanical sensitivity in the contralateral paw. The effect was fast and reversible and was associated with a decrease in the A to NA ratio (A/NA) in the adrenal gland and circulating blood, an A/NA that was elevated by CCI. 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (SKF29661) did not affect exocytosis evoked by Ca2+ entry as well as major ionic conductances (voltage-gated Na+, Ca2+, and K+ channels, nicotinic acetylcholine receptors) involved in stimulus-secretion coupling in chromaffin cells, suggesting that it acted by changing the relative content of the two adrenal catecholamines. Denervation of the adrenal medulla by surgical splanchnectomy attenuated mechanical allodynia in neuropathic animals, hence confirming the involvement of the adrenal medulla in the pathophysiology of the CCI model. Inhibition of PNMT appears to be an effective and probably safe way to modulate adrenal medulla activity and, in turn, to alleviate pain secondary to the injury of a peripheral nerve.
Highlights
Chromaffin cells from the adrenal medulla, the amplifying arm of the sympathetic nervous system (SNS), participate in stress responses by releasing the content of their secretory granules (mainly adrenaline (A), noradrenaline (NA), ATP, opioids, and chromogranins) into the bloodstream [1,2]
The two main observations communicated in this report are that: (i) inhibition of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts NA into A, reverts mechanical allodynia in the constriction injury of the sciatic nerve (CCI) model of neuropathic pain in the rat; and (ii) adrenal medulla denervation alleviates mechanical allodynia in the same experimental setting
Besides confirming that neuropathic pain acts as a stressor that mobilizes the sympathoadrenal arm of the SNS, our results imply that the stress response mediated by this arm influences pain behavior in a manner reminiscent of the notion of sympathetically maintained pain
Summary
Chromaffin cells from the adrenal medulla, the amplifying arm of the sympathetic nervous system (SNS), participate in stress responses by releasing the content of their secretory granules (mainly adrenaline (A), noradrenaline (NA), ATP, opioids, and chromogranins) into the bloodstream [1,2]. Stimulus-secretion coupling in chromaffin cells begins when ACh released from splanchnic nerve terminals binds to nicotinic acetylcholine receptors (nAChRs) located at the chromaffin cell plasma membrane. This leads to the opening of the cation channel associated with nAChRs with the ensued generation of a postsynaptic excitatory potential, which eventually triggers the discharge of an action potential. Ca2+ entry during action potentials is essential to stimulate the exocytotic release of A and NA from chromaffin cells [4]
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