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Journal of Neuroscience, Vol 9, 3380-3391, Copyright © 1989 by Society for Neuroscience
Sigma receptors regulate contractions of the guinea pig ileum longitudinal muscle/myenteric plexus preparation elicited by both electrical stimulation and exogenous serotonin
BG Campbell, MW Scherz, JF Keana and E Weber
Vollum Institute, Oregon Health Sciences University, Portland 97201.
Sigma receptors are specific, highly localized binding sites in limbic and
sensorimotor structures of the brain that interact with many psychotropic
drugs. These agents include the psychotomimetic benzomorphan opiates, the
psychotomimetic drug phencyclidine and its analogs, as well as numerous
typical and atypical antipsychotics such as haloperidol, chlorpromazine,
and the novel drugs BMY 14802 and rimcazole. So far, no physiological
function has been assigned to these binding sites. We have synthesized a
number of novel sigma receptor- active drugs derived from the selective
sigma ligand N,N'-di(o- tolyl)guanidine (DTG). DTG and its congeners were
found to inhibit contractions of the guinea pig ileal longitudinal
muscle/myenteric plexus (LMMP) preparation evoked by electrical
stimulation. In addition, the sigma ligands noncompetitively antagonized
contractions of the LMMP preparation evoked by serotonin (5-HT). The
5-HT-evoked contractions were found to be largely due to 5-HT's activation
of 5-HT3 receptors to release ACh. The activity of DTG congeners in
inhibiting electrically or 5-HT-evoked contractions of the LMMP highly
correlated with their potency to inhibit binding of both 3H-DTG and
(+)3H-3-PPP [3(3-OH-phenyl)-N-(1-propyl)piperidine] to sigma receptors in
guinea pig brain homogenates. Two DTG congeners that did not bind to sigma
receptors also showed no activity in the bioassay. Many other (but not all)
sigma receptor ligands showed a high correlation between their potency to
inhibit electrically evoked contractions of the LMMP and their sigma
receptor binding affinity. The benzomorphans (+)SKF 10,047 and
(+)cyclazocine potentiated electrically evoked contractions of the LMMP.
Sigma ligands also inhibited the contractions of the LMMP in the presence
of the opiate antagonist naloxone and in preparations in which opioid
receptors had been inactivated by treatment with the irreversible opiate
antagonist beta-chlornaltrexamine. Control experiments suggested that the
sigma ligands act via a neuronal mechanism to inhibit ACh release evoked by
electrical stimulation or by stimulation with 5-HT. These results suggest
that there are functional sigma receptors on cholinergic nerve terminals or
within the myenteric plexus and that these receptors can inhibit stimulated
ACh release through an opioid receptor-independent mechanism. However,
sigma receptor activation in the ileum has the same effect on ACh release
as activation of naloxone-sensitive opioid receptors. The LMMP may be an in
vitro bioassay system for characterizing the mechanism of action of sigma
receptors and for determining the biological efficacy of drugs known to
bind to sigma receptors in radioligand binding assays.
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