Neuroregulation of mucus secretion by opioid receptors and K_ATP and BK_Ca channels in ferret trachea in vitro

Abstract

1 Opioid agonists inhibit neurogenic mucus secretion in the airways. The mechanism of the inhibition is unknown but may be via opening of potassium (K + ) channels. We studied the e ect on neurogenic secretion in ferret trachea in vitro of the OP 1 receptor (formerly known as d opioid receptor) agonist [DPen 2,5 ]enkephalin (DPDPE), the OP 2 receptor (formely k) agonist U-50,488H, the OP 3 receptor (formerly m) agonist [D-Ala 2 , N-Me-Phe, Gly-ol 5 ]enkephalin (DAMGO), the ATP-sensitive K + (K ATP ) channel inhibitor glibenclamide, the large conductance calcium activated K + (BK Ca ) channel blocker iberiotoxin, the small conductance K Ca (SK Ca ) channel blocker apamin, the K ATP channel opener levcromakalim, a putative K ATP channel opener RS 91309, and the BK Ca channel opener NS 1619. Secretion was quanti®ed by use of 35 SO 4 as a mucus marker. 2 Electrical stimulation increased tracheal secretion by up to 40 fold above sham-stimulated levels. DAMGO or DPDPE (10 mM each) signi®cantly inhibited neurogenic secretion by 85% and 77%, respectively, e ects which were reversed by naloxone. U-50,488H had no signi®cant inhibitory e ect on neurogenic secretion, and none of the opioids had any e ect on ACh-induced or [Sar 9 ]substance Pinduced secretion. 3 Inhibition of neurogenic secretion by DAMGO or DPDPE was reversed by iberiotoxin (3 mM) but not by either glibenclamide or apamin (0.1 mM each). Iberiotoxin alone did not a ect the neurogenic secretory response. 4 Levcromakalim, RS 91309 or NS 1619 (3 nM ± 3 mM) inhibited neurogenic secretion with maximal inhibitions at 3 mM of 68%, 72% and 96%, respectively. Neither levcromakalim nor RS 91309 at any concentration tested signi®cantly inhibited acetylcholine (ACh)-induced secretion, whereas inhibition (60%) was achieved at the highest concentration of NS 1619, a response which was blocked by iberiotoxin. 5 Inhibition of neurogenic secretion by levcromakalim (3 mM) or RS 91309 (30 nM) was inhibited by glibenclamide but not by iberiotoxin. In contrast, inhibition by NS 1619 (30 nM and 3 mM) was blocked by iberiotoxin but not by glibenclamide. 6 We conclude that, in ferret trachea in vitro, OP 1 or OP 3 opioid receptors inhibit neurogenic mucus secretion at a prejunctional site and that the mechanism of the inhibition is via opening of BK Ca channels. Direct opening of BK Ca channels or K ATP channels also inhibits neurogenic mucus secretion. In addition, opening of BK Ca channels inhibits ACh-evoked secretion of mucus. Drugs which open BK Ca channels may have therapeutic anti-secretory activity in bronchial diseases in which neurogenic mechanisms and mucus hypersecretion are implicated in pathophysiology, for example asthma and chronic bronchitis.

Enkephalin, its precursor, processing enzymes, and receptor as part of a local opioid network throughout the respiratory system of lung cancer patients

“…A local opioid system has been implicated in the regulation of physiologic functions not only in the gut, spleen, and skin [1][2][3], but also-more recently-in the respiratory system, for example, modulating the tracheobronchial mucociliary clearance [4,5] and the smooth muscle bronchioconstrictive response [6]. Opioids-and more interestingly also opioid peptides-seem to have an impact on these physiologic respiratory functions [4][5][6].…”

KCO912: a potent and selective opener of ATP-dependent potassium (K ATP ) channels which suppresses airways hyperreactivity at doses devoid of cardiovascular effects

“…However, induction of AHR by immune complexes requires intact vagal nerves (Kristersson et al 1989) and sensory nerve activation has been implicated in the AHR generated by LPS (Loeffler et al 1997;Fozard and Mazzoni 2000) and ozone (Hazucha et al 1989;Ho and Lee 1998;Wu et al 2001). K ATP channel openers suppress activation of a variety of neurones (Ichinose and Barnes 1990;Lei et al 1993;Ramnarine et al 1998;Spina et al 1998) and it is possible that suppression of nervous activity underlies the effect of KCO912 to reverse AHR. However, the marked difference in potency of KCO912 and especially BRL 55834 in the immune complexes and ozone models of AHR in the guinea pig is difficult to reconcile with a common cellular site of action.…”

Endogenous Opioids as Mediators of Asthma

“…73 in ferret trachea is regulated by opioid receptors and A further study characterised endomorphin-1 and -2 (EM-1, EM-2) as potent inhibitors of EFS-induced K ATP and BK A channels in vitro. 83 It was concluded that OP 3 ( ) or OP 1 ( ) receptors inhibit neurogenic experimental effects of endogenous opioids. Studies using ORL 1 -modulatory drugs have not been demucus secretion at a prejunctional site and that the scribed so far, but may be expected in the light of all mechanism of the inhibition is via opening of BK recent findings on pulmonary effects of nociceptin.…”

“…83 Also, inhibitory effects of opioids on cigarette smoke, capsaicin and electrically-induced goblet cell ACKNOWLEDGEMENT secretion in guinea-pig trachea were reported, suggesting that opioids inhibit neurally-mediated goblet This study was supported by Biomed II. We would cell secretion via prejunctional OP 3 ( ) and OP 1 ( ) like to thank S. Wiegand, M. Scheibner, P. Hartmann receptors on cholinergic nerves and via OP 3 receptors and Q. T. Dinh for continuous help over the last years.…”