TY - JOUR
T1 - Pharmacological characterization of a 7-benzylidenenaltrexone-preferring opioid receptor in porcine ileal submucosa
AU - Townsend IV, De Wayne
AU - Brown, David R.
PY - 2003/10
Y1 - 2003/10
N2 - 1. In the intestine, opioids produce antidiarrhoeal and constipating actions that are mediated by enteric neurones. Through interactions with opioid receptors (ORs) on submucosal neurones, opioids suppress active ion transport evoked by transmural electrical stimulation (TES) in mucosa-submucosa sheets from the porcine ileum. In this study, we examined the pharmacological characteristics of the previously described OR, which is sensitive to the δ 1-OR antagonist 7-benzylidenenaltrexone and modulates neurogenic transepithelial ion transport in this tissue preparation. 2. Increases in short-circuit current (I sc, a measure of active anion transport) evoked by TES in ileal mucosa-submucosa sheets were inhibited by opioid agonists possessing high selectivity for either δ- or μ-ORs including [D-Pen 2,5]enkephalin (DPDPE), [D-Ala 2, Glu 4]deltorphin II, and [D-Ala 2, N-Me-Phe 4, Gly 5-ol]enkephalin (DAMGO). 3. As determined by the Schild analysis, the actions of these agonists were competitively inhibited by 7-benzylidenenaltrexone. The nonequilibrium μ-OR antagonist β-funaltrexamine inhibited the actions of DAMGO only at a high concentration (1 μM) but did not alter DPDPE or deltorphin II action. At concentrations up to 10 μM, the nonequilibrium δ-OR antagonist naltrindole 5′-isothiocyanate did not alter the actions of δ- or μ-OR agonists. 4. Radioligand binding analyses of neuronal homogenates from the ileal submucosa revealed that the nonselective OR ligand [ 3H]diprenorphine bound to two populations of specific binding sites. One of these sites possessed binding characteristics similar to the δ-OR. 5. In summary, neurogenic ion transport in the porcine intestine is modulated by an OR which shares pharmacological characteristics of both μ- and δ-ORs and may represent a novel receptor entity.
AB - 1. In the intestine, opioids produce antidiarrhoeal and constipating actions that are mediated by enteric neurones. Through interactions with opioid receptors (ORs) on submucosal neurones, opioids suppress active ion transport evoked by transmural electrical stimulation (TES) in mucosa-submucosa sheets from the porcine ileum. In this study, we examined the pharmacological characteristics of the previously described OR, which is sensitive to the δ 1-OR antagonist 7-benzylidenenaltrexone and modulates neurogenic transepithelial ion transport in this tissue preparation. 2. Increases in short-circuit current (I sc, a measure of active anion transport) evoked by TES in ileal mucosa-submucosa sheets were inhibited by opioid agonists possessing high selectivity for either δ- or μ-ORs including [D-Pen 2,5]enkephalin (DPDPE), [D-Ala 2, Glu 4]deltorphin II, and [D-Ala 2, N-Me-Phe 4, Gly 5-ol]enkephalin (DAMGO). 3. As determined by the Schild analysis, the actions of these agonists were competitively inhibited by 7-benzylidenenaltrexone. The nonequilibrium μ-OR antagonist β-funaltrexamine inhibited the actions of DAMGO only at a high concentration (1 μM) but did not alter DPDPE or deltorphin II action. At concentrations up to 10 μM, the nonequilibrium δ-OR antagonist naltrindole 5′-isothiocyanate did not alter the actions of δ- or μ-OR agonists. 4. Radioligand binding analyses of neuronal homogenates from the ileal submucosa revealed that the nonselective OR ligand [ 3H]diprenorphine bound to two populations of specific binding sites. One of these sites possessed binding characteristics similar to the δ-OR. 5. In summary, neurogenic ion transport in the porcine intestine is modulated by an OR which shares pharmacological characteristics of both μ- and δ-ORs and may represent a novel receptor entity.
KW - 7-benzylidenenaltrexone
KW - Antidiarrhoeal action
KW - Diprenorphine
KW - Enteric nervous system
KW - Intestinal secretion
KW - Naltrindole 5′-isothiocyanate
KW - Neurogenic ion transport
KW - β-funaltrexamine
KW - δ-opioid receptor
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U2 - 10.1038/sj.bjp.0705485
DO - 10.1038/sj.bjp.0705485
M3 - Article
C2 - 14534152
AN - SCOPUS:0242492579
SN - 0007-1188
VL - 140
SP - 691
EP - 700
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 4
ER -