Opioid modulation of non‐cholinergic neural bronchoconstriction in guinea‐pig in vivo

1 Electrical stimulation (1 ms, 5Hz, 80 V) for 5 or 15s at the level of C4-T1 in the spinal canal of artificially respired pithed guinea-pigs (which had received intravenously (i.v.) (+)-tubocurarine chloride 2 mg kg-1, atropine sulphate 2 mg kg-1 and pentolinium tartrate 5 mg kg') caused constriction of airways, indicated by increased insufflation pressure. 2 This non-cholinergic constriction was inhibited by morphine (1-3mg kg-1, i.v.), the peripherally acting p-receptor agonist, H-Tyr-D-Arg-Phe-Lys-NH2 (DALDA, 0.1-1mgkg-1, i.v.) or the a2-adrenoceptor agonist B-HT920 (1-3 mg kg-1, i.v.) 3 The effects of either morphine (3mg kg-1, i.v.) or DALDA (1 mg kg-1, i.v.) were inhibited by naloxone (3 mg kg-1, i.v.). Idazoxan (3 mg kg-1, i.v.) inhibited the anti-constrictor effect of B-HT920 (3 mg kg 1, i.v.), but not that of DALDA (0.1 mgkg-', i.v.).4 Thus activation of peripheral u-opioid receptors or X2-adrenoceptors inhibits airways constriction induced by non-cholinergic nerve stimulation in the pithed guinea-pig. This preparation therefore provides a further method for the in vivo examination of the effects of drugs on non-cholinergic tracheobronchial constrictor nerve function.

Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 49%

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Effects of morphine, H‐Tyr‐d‐Arg‐Phe‐Lys‐NH₂ (DALDA) and B‐HT920 on non‐cholinergic nerve‐mediated bronchoconstriction in pithed guinea‐pigs

Rechtman

Boura

King

et al. 1990

“…Opioids inhibit the NANC constrictor response in the guinea-pig in vivo and in the guinea-pig bronchi in vitro (Frossard & Barnes, 1987;Bartho et al, 1987;Belvisi et al, 1988) by preventing release of tachykinins, probably via a y-opioid receptor on airway afferent nerves.…”

Section: Introductionmentioning

confidence: 99%

Modulation of cholinergic neurotransmission in guinea‐pig airways by opioids

Belvisi

Stretton

Barnes

1990

Self Cite

1 Opioid receptors have been localised on sensory fibres in the vagus nerve and opioids have previously been shown to inhibit non-adrenergic, non-cholinergic (NANC) neurotransmission in guinea-pig bronchi in vitro and in vivo. We have now investigated whether an inhibitory effect could be demonstrated on cholinergic neurotransmission. 2 Electrical field stimulation (EFS) (8 Hz, 0.5 ms, 40 V for 20 s) produced only a rapid, cholinergic response in the upper trachea but in the lower trachea and main bronchi a cholinergic response which was atropine-sensitive and a longer lasting NANC contraction that was atropine-insensitive was demonstrated. This slow contraction could be blocked by tetrodotoxin and capsaicin pretreatment.3 [D-Ala2, NMePhe4, Gly-ol5]enkephalin (DAMGO), a selective p-opioid receptor agonist, inhibited the cholinergic response to EFS at 8 Hz in a dose-dependent manner in main bronchi (IC50 = 113 nm with a maximal inhibition of 35.7 + 5.6% 10 gM, n = 5). In the lower trachea, DAMGO inhibited the cholinergic response to a similar extent (inhibition of 35.8 + 3.5% at 1OpM, n = 5). However, DAMGO had no effect on the contractile response to exogenously applied acetylcholine in the main bronchi. By contrast, opioids had no inhibitory effect on cholinergic neurotransmission in the upper trachea. DAMGO (1 gM) inhibited the cholinergic response to EFS in a frequency-dependent manner in the main bronchi with greater inhibition at lower frequencies of stimulation. (10yM). U-50,488H, a K-receptor agonist, had no inhibitory effect on the cholinergic constrictor component in the main bronchi (10 M). 5 DAMGO also inhibited the NANC responses to EFS in the main bronchi in a dose-dependent manner (with an IC50 = 36 nm and a maximal inhibition of 63.4 + 8.3%, at 1 gM, n = 5). DAMGO had no effect on contractile responses to exogenously applied substance P (SP). DPDPE (10 pM) was less effective in inhibition of the NANC bronchoconstriction with a maximal inhibition of 29.2 + 4.2% (n = 7), and U-50,488H (1OpM) had no inhibitory effect. 6 After capsaicin pretreatment, which depleted sensory nerves of neuropeptides, the inhibitory effect of DAMGO (1 pM) on cholinergic constriction in main bronchi at 8 Hz was only 13.4 + 1.9% (n = 13) compared with 32.9 + 4.0% (n = 9) inhibition in vehicle-treated controls (P < 0.001). 7 Opioids may reduce the cholinergic neural responses in airways partly via an inhibitory action on excitatory NANC nerves and partly by a direct effect on cholinergic neurotransmission. The opioid receptor involved is of the p-opioid receptor subtype.

“…Morphine and opioid peptides inhibit neurally-mediated broncho-constriction (Frossard & Barnes, 1987;Bartho et al, 1987;Belvisi et al, 1988) and plasma exudation (Belvisi et al, 1989) in guinea-pig airways, and mucus secretion in human bronchi by blocking the release of tachykinins from capsaicin-sensitive sensory nerves. Opioids have also been shown to inhibit the cholinergic component of airway excitation in guinea-pigs (Johansson et al, 1989;Belvisi et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Differential inhibitory effects of opioids on cigarette smoke, capsaicin and electrically‐induced goblet cell secretion in guinea‐pig trachea

Kuo

Rohde

Barnes

et al. 1992

Self Cite

1 Goblet cell secretion in guinea-pig airways is under neural control. Opioids have previously been shown to inhibit neurogenic plasma exudation and bronchoconstriction in guinea-pig airways. We have now examined the effects of morphine and opioid peptides on tracheal goblet cell secretion induced by either electrical stimulation of the cervical vagus nerves, exogenous capsaicin, or acute inhalation of cigarette smoke. The degree of goblet cell secretion was determined by a morphometric method and expressed as a mucus score which is inversely related to mucus discharge. 2 Morphine, 1 mg kg-1, completely blocked goblet cell secretion induced by electrical stimulation of the vagus nerves. Morphine also inhibited the response to cigarette smoke given either at a low dose (10breaths of 1:10 diluted in air), which principally activates cholinergic nerves, or at a high dose (20 breaths of undiluted), which activates capsaicin-sensitive sensory nerves, by 100% and 73% respectively. In contrast, morphine had no significant inhibitory effect on capsaicin-induced goblet cell secretion. The inhibitory effect of morphine was reversed by naloxone. Pen2, D-Pen5]enkephalin (DPDPE) respectively, caused a dose-related inhibition of low dose cigarette smoke-induced goblet cell discharge, with DPDPE more potent than DAMGO. A K-receptor agonist, trans-3,4-dichloro-N-methyl-N-(2-(1-pyrollidinyl)cyclohexyl) benzeneacetamine (U-50,488H), had no inhibitory effect. DPDPE had no inhibitory effect on goblet cell secretion induced by exogenous methacholine. 4 DAMGO dose-dependently blocked the response to high dose cigarette smoke with a maximal inhibition of 95% at 2 x 10-7mol kg-'. Neither DPDPE nor U-50,488H had any significant inhibitory effect.The increase in goblet cell secretion induced by exogenous substance P was not affected by DAMGO. 5 We conclude that opioids inhibit neurally-mediated goblet cell secretion via actions at prejunctional band p-receptors on cholinergic nerves and at p-receptors on sensory nerve endings, and that capsaicin activation of sensory nerves is via a different mechanism from that of electrical or cigarette smoke activation.