NEUROREGULATION OF MUCUS SECRETION BY OPIOID RECEPTORS AND K-ATP AND BKCA CHANNELS IN FERRET TRACHEA IN-VITRO

1 Opioid agonists inhibit neurogenic mucus secretion in the airways. T he mechanism of the inhibition is unknown but may be via opening of po tassium (K+) channels. We studied the effect on neurogenic secretion i n ferret trachea in vitro of the OP1 receptor (formerly known as delta opioid receptor) agonist [D-Pen(2,5)]enkephalin (DPDPE), the OP2 rece ptor (formely kappa) agonist U-50,488H, the OP3 receptor (formerly mu) agonist [D-Ala(2), N-Me-Phe, Gly-ol(5)]enkephalin (DAMGO), the ATP-se nsitive K+ (K-ATP) channel inhibitor glibenclamide, the large conducta nce calcium activated K+ (BKCa) channel blocker iberiotoxin, the small conductance K-Ca (SKCa) channel blocker apamin, the K-ATP channel ope ner levcromakalim, a putative K-ATP channel opener RS 91309, and the B KCa channel opener NS 1619. Secretion was quantified by use of (SO4)-S -35 as a mucus marker. 2 Electrical stimulation increased tracheal sec retion by up to 40 fold above sham-stimulated levels. DAMGO or DPDPE ( 10 mu M each) significantly inhibited neurogenic secretion by 85% and 77%, respectively, effects which were reversed by naloxone. U-50,488H had no significant inhibitory effect on neurogenic secretion, and none of the opioids had any effect on ACh-induced or [Sar(9)]substance P-i nduced secretion. 3 Inhibition of neurogenic secretion by DAMGO or DPD PE was reversed by iberiotoxin (3 mu M) but not by either glibenclamid e or apamin (0.1 mu M each). Iberiotoxin alone did not affect the neur ogenic secretory response. 4 Levcromakalim, RS 91309 or NS 1619 (3 nM- 3 mu M) inhibited neurogenic secretion with maximal inhibitions at 3 m u M of 68%, 72% and 96%, respectively. Neither levcromakalim nor RS 91 309 at any concentration tested significantly inhibited acetylcholine (ACh)-induced secretion, whereas inhibition (60%) was achieved at the highest concentration of NS 1619, a response which was blocked by iber iotoxin. 5 Inhibition of neurogenic secretion by levcromakalim (3 mu M ) or RS 91309 (30 nM) was inhibited by glibenclamide but not by iberio toxin. In contrast, inhibition by NS 1619 (30 nM and 3 mu M) was block ed by iberiotoxin but not by glibenclamide. 6 We conclude that, in fer ret trachea in vitro, OP1 or OP3 opioid receptors inhibit neurogenic m ucus secretion at a prejunctional site and that the mechanism of the i nhibition is via opening of BKCa channels. Direct opening of BKCa chan nels or K-ATP channels also inhibits neurogenic mucus secretion. In ad dition, opening of BKCa channels inhibits ACh-evoked secretion of mucu s. Drugs which open BKCa channels may have therapeutic anti-secretory activity in bronchial diseases in which neurogenic mechanisms and mucu s hypersecretion are implicated in pathophysiology, for example asthma and chronic bronchitis.