Enkephalin Receptors in the Emetic Chemoreceptor Trigger Zone of the Dog

Abstract

IThe emetic action of Met-enkephalin, morphine and naloxone was studied following their administration into the cerebral ventricles of dogs through chronically implanted cannulae and the effect on the responses of ablating the chemoreceptor trigger zone (CTZ) was investigated. The opiate antagonist, naloxone, was used to determine the role of enkephalin receptors in emetic responses.2 Administration of Met-enkephalin (1.0 pg/kg) into the IVth ventricle regularly evoked emesis with an average latency of 35 s. A dose of morphine (2.5 pg/kg) which was five times larger was required for a consistent emetic response when introduced into the lateral cerebral ventricle (i.c.v.) as compared to the dose required by the IVth ventricular route. The latency of emetic responses by the latter route of injection of morphine was shorter. This is in accord with an action of morphine on the emetic CTZ. 3 After bilateral ablation of the CTZ, intraventricular injections of Met-enkephalin and morphine failed to produce emesis even when given in doses that were 5 to 10 times the dose which regularly elicited emesis in animals with intact CTZ. The emesis produced in dogs by intraventricular Metenkephalin and morphine is thus fully accounted for by an action on the CTZ. 4 Naloxone (i.c.v.) in doses up to 10.0 jg/kg did not cause emesis. However, higher doses of naloxone elicited dose-dependent emesis in dogs. The 100% emetic dose of naloxone was found to be 160 pg/kg and the latency of emesis was 180 s. Unlike Met-enkephalin and morphine, naloxone continued to elicit emesis in CTZ-ablated animals. 5 Pretreatment with intraventricular naloxone (1 to 8 jg/kg) blocked the emetic responses induced by intraventricular Met-enkephalin and morphine but not that to apomorphine. The selective protective action of the opiate antagonist against Met-enkephalin and morphine supports the presence of enkephalin receptors in the emetic CTZ.

Peptideinduced Emesis in Dogs: Possible Relevance to Radiation-Induced Emesis.

“…The peptides which had no effect or produced emesis accompanied by other systemic effects are unlikely candidates, since the emesis induced by radiation in animals or man is not accompanied by a marked gastrointestinal activation. It is of interest that enkephalin (0.05 mg/kg) did not produce emesis, even though vomiting with narcotic agents is common in man, and emesis has been demonstrated in dogs with intraventricular injection of enkephalin (1). Possibly the concentration we used was too low for this effect to be seen.…”

Evidence for a Motion Sickness Agent in Cerebrospinal Fluid

“…Dopa mine and L-dopa [Lotti and Clark, 1974], histamine [Bhargava and Dixit, 1968] and metenkephalin [Bhargava et al, 1981] are among these putative candidates. Experi ments are needed to track concentrations of these elements and others in the CSF during the motion sickness process.…”

Pharmaceutical interventions facilitate premedication and prevent opioid-induced constipation and emesis in cancer patients

“…In particular, constipation and nausea/vomiting are the most frequent side effects induced by opioid analgesics, since the minimal doses that induce constipation, nausea, and vomiting are even lower than those causing analgesia [7][8][9]. Opioid analgesics inhibit peristalsis of the small intestine through activation of opioid μ-and κ-receptors [10], which leads to constipation, while opioids cause nausea and vomiting through different mechanisms, including stimulation of the chemoreceptor trigger zone [11] and inhibition of gut motility [12]. Less common side effects are drowsiness, urinary retention, delirium, and respiratory depression [13][14][15].…”