Specific Opiate Receptors Research Articles

Possible role of proenkephalin in psoriasis.

Psoriasis is a common chronic skin disease that can also affect the mucous membranes and joints. It is multifactorial in origin, occurring in genetically predisposed individuals, and triggered by various endogenous and exogenous factors. Proenkephalin (PENK) is an endogenous opioid polypeptide hormone that acts on specific opiate receptors found on nerve and mucosal cells, and on various cells in the immune system. PENK receptors are expressed on skin cells, and their activation can regulate keratinocyte and melanocyte activities. PENK expression has been found to be increased in keratinocytes in psoriatic skin, and together with its inflammatory basis, this suggests that PENK may be regulated by inflammatory stimuli. To assess the possible role of PENK in the pathogenesis of psoriasis and to assess if it is related to the severity of psoriatic lesions. Serum and tissue PENK levels were estimated in 20 patients with psoriasis vulgaris, and compared with those of 20 healthy controls (HCs). PENK levels were found to be significantly increased both in serum and in psoriatic lesions in patients compared with HCs. No significant correlation was found between PENK levels and patient age, disease duration or disease severity (Psoriasis Area and Severity Index). Our results support the role of PENK in the aetiopathogenesis of psoriasis, and indicate that giving anti-PENK drugs in addition to current antipsoriatic therapies might be of value in treating this common chronic skin disease.

Involvement of histaminergic mechanisms in the cataleptogenic effect of morphine in mice.

Intraperitoneally administered morphine induced catalepsy in mice. Morphine pretreatment however, failed to antagonize apomorphine-induced cage climbing behaviour thereby ruling out the possibility of its possessing DA receptor blocking activity. Pretreatment with L-histidine, a precursor of histamine, and atropine, potentiated the cataleptic effect of morphine whilst pretreatment with chlorcyclizine, an H1 receptor blocker, and naloxone, a morphine antagonist, antagonized morphine-catalepsy. Pretreatment with metiamide, an H2 receptor blocker, and methysergide, a 5-HT antagonist, did not significantly alter the cataleptic effect of morphine. The results with L-histidine and chlorcyclizine suggest an involvement of central histaminergic mechanisms in the cataleptogenic effect of morphine in mice. Further, as the cataleptic effect of morphine was also antagonized by naloxone it appears that the interaction of morphine with the central histaminergic mechanisms is mediated through specific opiate receptors.

The depressant action of morphine on transmission at a skeletal neuromuscular junction is non-specific.

Abstract The depressant actions of apomorphine, etorphine, dextromoramide, laevomoramide, naloxone, codeine, morphine and nalorphine have been examined on the rat diaphragm preparation. Their descending order of potency (in the order given above) differed greatly from that published for activity at specific opiate receptors. The depressant action of morphine was not antagonized by naloxone. The stereoisomers dextro- and laevomoramide were equipotent in depressing the preparation. On the transmurally stimulated guinea-pig ileum preparation the depressant action of dextromoramide was antagonized by naloxone. Laevomoramide was 10 000 times less potent than its (+)-isomer, and was not antagonized by naloxone. It is concluded that the effects of narcotic analgesics on transmission at a skeletal neuromuscular junction are not mediated via opiate receptors.

25-HYDROXYVITAMIN D, DEMENTIA, AND CEREBROVASCULAR PATHOLOGY IN ELDERS RECEIVING HOME SERVICES

Data concerning the effects of morphine on human pancreatic secretion are fragmentary and inconclusive. In the present study, we evaluated the effects of morphine on pure pancreatic secretion in nine subjects with external transduodenal drainage of the main pancreatic duct performed after biliary tract surgery. Intravenous infusion of a small dose of morphine, 40 microgram/kg/h, during pancreatic stimulation with secretin and cholecystokinin, caused a significant increase in volume, bicarbonate, and calcium secretion, and a significant decrease in protein secretion. The stimulatory effect on water and electrolyte secretion was rapid and much more pronounced, reaching about 45-50% of the control levels, whereas the inhibition of protein output was slightly delayed and of lesser magnitude, reaching about 20-25% of the control values. Both effects were long-lasting. The addition of naloxone, potent opiate antagonist, prevented in part the effects of morphine on pancreatic secretion, suggesting that specific opiate receptors might be involved in these effects.

Overview and historical perspective of four papers presented on research related to the endogenous opioid system

Overview and historical perspective of four papers presented on research related to the endogenous opioid system

Buprenorphine in the Treatment of Opiate Dependence: Its Pharmacology and Social Context of Use in the U.S.

Buprenorphine's physiological effects are produced when it attaches to specific opiate receptors that are designated mu, kappa, or delta. Buprenorphine, a partial agonist at the mu receptor and an antagonist at the kappa receptor, produces typical morphine-like effects at low doses. At higher doses, it produces opiate effects that are less than those of full opiate agonists. Knowledge of the physiological effects of opiate receptors and the way they interact with opiate agonists, partial opiate agonists, and opiate antagonists is fundamental to understanding the safety and efficacy of buprenorphine in treatment of pain and opiate addiction. Knowledge of the historical and social context of opiate agonist treatment of opiate dependence is fundamental to understanding how nonpharmacological factors may limit the clinical adoption and utility of a safe and effective medication in treatment of opiate dependence. This article reviews, the pharmacology of sublingual buprenorphine and the historical context of opiate agonist therapy; delineates classes of opiate receptors and their interaction with opiate agonists, partial agonists, and antagonists; and describes the commercially available pharmaceutical formulations of buprenorphine. It focuses on sublingual buprenorphine tablets, Subutex® and Suboxone®, the FDA-approved formulations of buprenorphine for treatment of opiate dependence. Sublingual buprenorphine, and the combination of sublingual buprenorphine/naloxone, have unique pharmacological properties that make them a logical first-line intervention in the treatment of opioid dependence.

Milk Bioactive Peptides and β-Casomorphins Induce Mucus Release in Rat Jejunum

Intestinal mucus is critically involved in the protection of the mucosa. An enzymatic casein hydrolysate and beta-casomorphin-7, a mu-opioid peptide generated in the intestine during bovine casein digestion, markedly induce mucus discharge. Because shorter mu-opioid peptides have been described, the effects of the opioid peptides in casein, beta-casomorphin-7, -6, -4, -4NH2 and -3, and of opioid neuropeptides met-enkephalin, dynorphin A and (D-Ala2,N-Me-Phe4,glycinol5)enkephalin (DAMGO) on intestinal mucus secretion were investigated. The experiments were conducted with isolated perfused rat jejunum. Mucus secretion under the influence of beta-casomorphins and opioid neuropeptides administered intraluminally or intra-arterially was evaluated using an ELISA for rat intestinal mucus. Luminal administration of beta-casomorphin-7 (1.2 x 10(-4) mol/L) provoked a mucus discharge (500% of controls) that was inhibited by naloxone, a specific opiate receptor antagonist. Luminal beta-casomorphin-6, -4 and -4NH2 did not modify basal mucus secretion, whereas intra-arterial administration of beta-casomorphin-4 (1.2 x 10(-6) mol/L) induced a mucus discharge. In contrast, intra-arterial administration of the nonopioid peptide beta-casomorphin-3 did not release mucus. Among the opioid neuropeptides, intra-arterial infusion of Met-enkephalin or dynorphin-A did not provoke mucus secretion. In contrast, beta-endorphin (1.2 x 10(-8) to 1.2 x 10(-6) mol/L) induced a dose-dependent release of mucus (maximal response at 500% of controls). DAMGO (1.2 x 10(-6) mol/L), a mu-receptor agonist, also evoked a potent mucus discharge. Our findings suggest that mu-opioid neuropeptides, as well as beta-casomorphins after absorption, modulate intestinal mucus discharge. Milk opioid-derived peptides may thus be involved in defense against noxious agents and could have dietary and health applications.

Assessment of SNC 80 and Naltrindole Within a Conditioned Taste Aversion Design

Although compounds with relative selectivity for the mu and kappa opiate receptors subtypes have been reported to condition taste aversions, it is not known whether systemically administered delta compounds have the ability to produce aversions. To that end, female Long-Evans rats were adapted to water deprivation and were given pairings of a novel saccharin solution and various doses of the selective delta agonist SNC 80 (0.32–10.0 mg/kg; Experiment 1) or the selective delta antagonist naltrindole (1.0–18.0 mg/kg; Experiment 2). For comparison, the relatively selective mu agonist morphine (Experiment 1) and mu antagonist naloxone (Experiment 2) were assessed under identical conditions. Both SNC 80 (Experiment 1) and naltrindole (Experiment 2) were effective as unconditioned stimuli within this design, inducing dose-dependent taste aversions with repeated conditioning trials. Although at no dose did animals injected with SNC 80 differ from those injected with morphine, aversions induced by SNC 80 were acquired at a faster rate than those induced by morphine. Subjects injected with naloxone drank significantly less than those injected with naltrindole at the 10 mg/kg dose, and aversions induced by naloxone at 5.6 and 10 mg/kg were acquired at a faster rate than those induced by naltrindole. Although the basis for opioid agonist- and antagonist-induced taste aversions is not known, the differences between aversions induced by SNC 80 and naltrindole and those induced by morphine and naloxone, respectively, may be a function of their relative selectivity for specific opiate receptor subtypes.

Immunoneutralization of Endogenous Opioid Peptides Prevents the Suckling-Induced Prolactin Increase and the Inhibition of Tuberoinfundibular Dopaminergic Neurons

Previous studies have shown that the endogenous opioid peptides, acting at specific opiate receptor subtypes, are involved in the suckling-induced prolactin secretory response. The prolactin increase elicited by suckling is due, at least in part, to an inhibition of tuberoinfundibular dopaminergic (TIDA) neurons in the hypothalamus. We investigated the effects of immunoneutralization of dynorphin, leu-enkephalin and met-enkephalin on the suckling-induced prolactin increase and on the activity of the TIDA neurons in lactating female rats between days 7 and 12 postpartum. Rats were injected into the right lateral ventricle with antiserum specific for one of these three peptides. Control rats were administered equal amounts of immunoglobulin proteins. Suckling produced a profound and significant increase in prolactin levels, as well as a decrease in DOPA accumulation in the median eminence of lactating rats. Administration of immunoglobulin concentrations of up to 3.6 µg did not inhibit the prolactin secretory response to the suckling stimulus and did not prevent the suckling-induced inhibition of TIDA neurons. Antisera to all three endogenous opioid peptides abolished the suckling-induced prolactin increase and prevented the inhibition in DOPA accumulation in the median eminence. Thus, the endogenous opioid peptides, dynorphin, leu-enkephalin and met-enkephalin, are essential for the prolactin secretory response to suckling and inhibition of TIDA neuronal activity is at least one of the mechanisms of action utilized by these peptides.

Opioid peptides inhibit the action of oestradiol on human myometrial cells in culture.

The effect of opioid peptides on cultured, oestradiol-stimulated human myometrial cells was examined. Oestradiol increased cell densities in mixed-cell (smooth muscle cells + stromal fibroblasts) cultures by 40%. This oestradiol-induced stimulation of cell proliferation was decreased to control values by D-met2-pro5-enkephalinamide. The half-effective inhibitory concentration of enkephalinamide was 0.3 nmol/l. The opioid-induced inhibition of cell proliferation was blocked completely by the specific opiate receptor antagonist naloxone, while naloxone did not have any effect on its own. This opioid effect was mediated dominantly by the mu opiate receptor. The optimal concentration for oestradiol to stimulate uterine cell proliferation was 2.2 nM. The basal rate of cell proliferation was not affected by enkephalinamide. In saturation experiments, the parameters of specific [3H]-naloxone binding were: dissociation constant = 1.02 nM, maximal binding capacity = 2910 binding sites/cell, Hill coefficient = 1.029. In human myometrial pure smooth muscle cell cultures, oestradiol decreased the proliferation of cells. Progesterone potentiated these oestradiol effects, but had no effect on its own. Enkephalinamide was also able to block the effects of oestradiol, but naloxone did not antagonize it. In summary, here we present a novel inhibitory role of endogenous opioid peptides in the regulation of cell growth and proliferation in the human uterus.

Endogenous opioid system in developing normal and jimpy oligodendrocytes: mu and kappa opioid receptors mediate differential mitogenic and growth responses.

The early development of both neurons and neuroglia may be modulated by signaling through opioid mediated pathways. Neurons and astroglia not only express specific types of opiate receptors, but also respond functionally to opioids with altered rates of proliferation and growth. The present study was undertaken to determine if opioids also modulate development of the other major CNS macroglial cell, the oligodendrocyte (OL). Using well-characterized polyclonal antibodies specific for delta-, kappa-, and mu-opiate receptors, OLs grown in vitro were shown to express mu-receptors at a very immature stage prior to expression of kappa-receptors. This developmentally regulated sequence differs from the pattern of expression in neurons and astroglia. delta-receptors are apparently absent from cultured OLs. OLs also have physiologic responses to selective mu- and kappa-receptor agonists and antagonists. Exposure of relatively immature O4+ OLs to the mu-receptor agonist PL017 [H-Tyr-Pro-Phe(N-Me)-D-Pro-NH2] resulted in a significant enhancement in the rate of DNA synthesis. This effect, which was not observed in more mature MBP+ OLs, was entirely blocked by the antagonist naloxone. Although the kappa-receptor pathway appeared to be uninvolved in controlling proliferation, the kappa-receptor antagonist nor-binaltorphimine significantly increased the size of myelin-like membranes produced by the cultured OLs. Interestingly, OLs derived from the jimpy mouse, a mutant characterized by an almost complete lack of CNS myelin and premature death of OLs, were found to be deficient in kappa-opiate receptors. Our findings clearly show that OLs not only express specific opiate receptors, but also respond to changes in their level of stimulation in ways that could profoundly impact nervous system morphology and function. If opiate receptors are expressed by OLs in vivo, their pharmacological manipulation might provide a novel pathway for modulating OL and myelin production both during development and in demyelinated conditions.

Opioid receptors: some perspectives from early studies of their role in normal physiology, stress responsivity, and in specific addictive diseases.

The early history of research on the possible existence of specific opioid receptors and on developing a new form of pharmacotherapy for the treatment of heroin addiction in New York City, from 1960-1973, along with the special relationships between two leading scientists conducting these research efforts, Dr. Eric Simon and Dr. Vincent P. Dole Jr., are presented in a historical perspective. The linkage of these early efforts and the subsequent identification and the elucidation of the effects of exogenous opiates acting at specific opiate receptors in human physiology, including some findings from perspective studies of heroin addicts at time of entry to and during methadone maintenance treatment, are presented in the context of the important clues which thereby were provided concerning the possible roles of the endogenous opioids in normal mammalian physiology. From many of these early clinical research findings and studies in animal models, the hypothesis that the endogenous opioids system may play an important role in stress responsivity was formulated along with the related hypothesis, first presented in the early 1970s, that an atypical responsivity to stress and stressors might be involved in the acquisition and persistence of, and relapse to specific addictive diseases, including heroin addiction, cocaine dependency and alcoholism. More recent studies of the possible involvement of the specific opioid receptors in these three addictive diseases-heroin addiction, cocaine addiction and alcoholism-from our laboratory are discussed in a historical perspective of the development of these ideas from the early research findings of not only Dr. Eric Simon, but his numerous colleagues in opioid research in the United States and throughout the world.

Insulin-induced hypoglycemia decreases luteinizing hormone secretion in the castrated male rat: involvement of opiate peptides.

Insulin-induced hypoglycemia (IIH) has been reported to inhibit luteinizing hormone (LH) secretion in ovariectomized ewes as well as in intact or gonadectomized female rhesus monkeys. An infusion of naloxone, a specific opiate receptor antagonist, while able to prevent this inhibitory effect in ewes, was ineffective in monkeys, suggesting a difference in the mechanisms involved in the response to IIH in these two species. The present study was designed to investigate the influence of this stimulus on the dynamics of LH release and the possible activation of an opioidergic pathway in the long-term castrated male rat. Blood samples were collected every 7 min, for several hours, in freely-moving rats bearing a jugular cannula. The intravenous injection of 0.4 IU of insulin triggered an acute hypoglycemia and reduced LH release. In contrast, during a continuous intravenous naloxone infusion (0.5 mg/kg/h), insulin, while still lowering the glycemia, failed to affect the LH secretory pattern. In a control experiment, naloxone infusion alone had no significant effect on mean LH concentration and pulse intervals. These experiments indicate that, in long-term gonadectomized male rats, IIH impairs the LH secretory pattern, and that endogenous opioid peptides are involved in this response.

Functional studies on opioid receptor heterogeneity in the central nervous system

Although compounds with relative selectivity for the mu and kappa opiate receptors subtypes have been reported to condition taste aversions, it is not known whether systemically administered delta compounds have the ability to produce aversions. To that end, female Long-Evans rats were adapted to water deprivation and were given pairings of a novel saccharin solution and various doses of the selective delta agonist SNC 80 (0.32–10.0 mg/kg; Experiment 1) or the selective delta antagonist naltrindole (1.0–18.0 mg/kg; Experiment 2). For comparison, the relatively selective mu agonist morphine (Experiment 1) and mu antagonist naloxone (Experiment 2) were assessed under identical conditions. Both SNC 80 (Experiment 1) and naltrindole (Experiment 2) were effective as unconditioned stimuli within this design, inducing dose-dependent taste aversions with repeated conditioning trials. Although at no dose did animals injected with SNC 80 differ from those injected with morphine, aversions induced by SNC 80 were acquired at a faster rate than those induced by morphine. Subjects injected with naloxone drank significantly less than those injected with naltrindole at the 10 mg/kg dose, and aversions induced by naloxone at 5.6 and 10 mg/kg were acquired at a faster rate than those induced by naltrindole. Although the basis for opioid agonist- and antagonist-induced taste aversions is not known, the differences between aversions induced by SNC 80 and naltrindole and those induced by morphine and naloxone, respectively, may be a function of their relative selectivity for specific opiate receptor subtypes.

A haemodynamic comparison of intrathecal morphine and sufentanil supplemented with general anaesthesia for abdominal aortic surgery

The haemodynamic changes associated with intrathecal morphine (IM) compared to intrathecal sufentanil (IS) as a supplement to general anaesthesia for elective bypass grafting in patients with aortoiliac occlusive disease were studied. Thirty-six, ASA Grade 2, patients randomly received morphine hydrochloride (0.1%) 50 micrograms kg-1 (n = 18) or undiluted sufentanil, 150 micrograms (n = 18) intrathecally at T12-L1, combined with light general anaesthesia. Haemodynamics were measured before and after endotracheal intubation, abdominal incision, aortic cross-clamping and the first revascularisation. The major differences were recorded after abdominal incision. Heart rate, systemic blood pressure and coronary perfusion pressure were significantly lower in the IS group. The probable cause was greater systemic absorption of sufentanil and its faster binding to the specific opiate receptors, resulting in a more efficacious supraspinal and spinal blockade during the first surgical period. However, both opioids provided adequate analgesia during the whole surgical procedure.

Mode of action of interleukin-1 in suppression of pituitary LH release in castrated male rats

These studies were undertaken to elucidate the mechanisms whereby the cytokine, Interleukin (IL-1) suppresses pituitary LH release in orchidectomized rats. Since LH secretion in pulsatile in castrated rats, the effects of IL-1 on the components of the LH pulsatility were assessed. Intracerebroventricular (i.c.v.) administration of IL-1α or IL-1β suppressed LH release, but IL-1β was relatively more effective than IL-1α in terms of the onset (IL-1β = 30min; IL-1α = 105min) as welk as the magnitude and duration of LH suppression. Further, the marked suppression of LH secretion in IL-1β-treated rats was found to be due to significant reductions both in the frequency and amplitude of LH episodes. We next evaluated whether the IL-1β-induced suppression of LH release was mediated by either of the two inhibitory hypothalamic peptidergic systems, corticotrophin releasing hormone (CRH) and endogenous opioid peptides (EOP). Passive immunoneutralization of CRH by i.c.v. administration of a specific CRH-antibody, either once at 15 min or twice at 75 and 15 min before IL-1β injection, failed to block the suppressive effects of IL-1β on LH release. Similarly, pharmacological blockade of CRH by i.c.v. injection of the CRH receptor antagonist, α-helical CRH 9–41 15 min before IL-1β was ineffective. However, i.v. infusion of the opiate receptor antagonist, naloxone, which on its own had no effect on LH secretion, counteracted the inhibitory effects of IL-1β. To further identify the opiate receptor subtype involved, we utilized specific opiate receptor subtype antagonists. We observed that neither blockade of δ receptors with naltrindole, nor blockade of κ receptors with nor-binaltorphimine dihydrochloride, altered the course of LH suppression seen after IL-1β injection. However, prior blockade ofμ 1 opiate receptors wit β-funaltrexamine hydrochloride, completely reversed the inhibitory effects of IL-1β on LH release. These results show that IL-1β suppresses both the frequency and amplitude of LH discharge in two-week castrated rats. Further pharmacologic evidence shows that IL-1ß-induced suppression of LH secretion may involve stimulation of hypothalamic endogenous opioids which presumably act via the hypothalamicμ 1 opiate receptor subtype, and that stimulation of hypothalamic CRH release may not be essential in manifestation of the inhibitory effects of IL-1ß on LH release.

Lipolytic effect of beta-endorphin in human fat cells

Recently, a role of β-Endorphin on peripheral tissue metabolism has been suggested. A lipolytic effect of β-Endorphin has been observed both in vivo and in vitro in animals but, at present, there is no evidence for a similar effect in humans. In this study, we investigated the lipolytic effect of β-Endorphin in isolated human adipocytes. B-Endorphin induced a significant increase in glycerol release in isolated human fat cells. Naloxone was able to inhibit the β-Endorphin-induced lipolysis. The opioid antagonist alone had no effect on basal lipolysis and on Epinephrine-stimulated lipolysis when administered together with this hormone. Our results suggest that β-Endorphin may play a role on lipolysis also in human fat cells and that this effect may be mediated by a specific opiate receptor.

Effect of dalargin, a synthetic leu-enkephalin analogue on synaptic transmission in the Lorenzini ampullae of rays

Effects of dalargin, a synthetic leu-enkephalin analogue and its antagonist naloxone on synaptic transmission in afferent synapses of ray electroreceptors were investigated using an isolated preparation of Lorenzini ampullae from Black sea rays. It was shown that dalargin (10−6–10−10 mole liter) both decreased background activity and evoked activity of an afferent fiber in a dose-dependent manner. Naloxone (10−5 mole/liter) also inhibited afferent impulsation and completely blocked responses of the Lorenzini ampullae to dalargin application. L-glutamate-induced excitatory responses were reduced in the presence of dalargin. It is suggested that the modulatory action of dalargin on glutamatergic synaptic transmission in the Lorenzini ampullae is exerted via specific opiate receptors.

Management of postoperative pain by continuous epidural infusion of analgesics

The anatomy and physiology of the epidural space and the mechanism of action, sites of action, and pharmacokinetics of analgesics administered by continuous epidural infusion are reviewed, and the efficacy, adverse effects, and postoperative indications for use of analgesics administered by this route are discussed. Narcotics selectively block pain conduction by occupying specific opiate receptors in the spinal cord. Local anesthetics provide analgesia by axonal membrane blockade; they also can produce nonselective sympathetic and somatic (sensory and motor) blockade in addition to analgesia. A narcotic-local anesthetic mixture should provide an additive analgesic effect, without an increase in the incidence of adverse effects. Comparative efficacy studies have shown that continuous epidural infusions of narcotics, local anesthetics, and narcotic-local anesthetic combinations, when used appropriately, may produce better analgesia than conventional bolus methods of pain relief. Continuous epidural infusions also offer a safety advantage over intermittent epidural injections because peak and trough levels of the analgesic agent are avoided. Adverse effects of epidurally administered narcotics include respiratory depression, pruritus, urinary retention, nausea and vomiting, and sedation. Adverse effects of epidurally administered local anesthetics include urinary retention, hypotension, numbness, motor weakness, tachyphylaxis, and, rarely, systemic toxicity. The cost of epidurally administered drugs is substantially higher than that for i.m. or i.v. narcotic analgesia, but this cost may be offset by other benefits such as a shorter hospital stay. Current studies suggest superior analgesia for the majority of surgical procedures with continuous epidural analgesia infusions compared with more traditional methods of providing analgesia.

Dopamine release from interplexiform cells in the retina: effects of GnRH, FMRFamide, bicuculline, and enkephalin on horizontal cell activity

In teleost fish, dopaminergic interplexiform cells provide an intraretinal centrifugal pathway from the inner to the outer plexiform layer, where they make abundant synapses on cone-related horizontal cells. The interplexiform cells receive all their input in the inner plexiform layer from centrifugal fibers and amacrine cells. In fish, centrifugal fibers contain gonadotropin hormone-releasing hormone (GnRH)-like and FMRFamide-like peptides (Munz et al., 1982; Stell et al., 1984), whereas amacrine cells contain a variety of neuroactive substances, including a number of peptides. In this study, we examined the effects of GnRH, FMRFamide, bicuculline, and enkephalin on horizontal cell activity in the white perch retina in an attempt to understand the synaptic inputs to the interplexiform cells. When the retina was superfused with Ringer's solution containing GnRH, horizontal cells depolarized (approximately 10 mV), and their responses to small spots increased, whereas their responses to full-field lights decreased. Thus, GnRH closely mimicked the effects of dopamine on horizontal cells. The GnRH antagonist [D-Phe2, Pro3, D-Phe6]-GnRH blocked the effects of GnRH, as did haloperidol. GnRH also had no effect on horizontal cells in retinas treated with 6-hydroxydopamine. The results indicate that GnRH acts by stimulating the release of dopamine from interplexiform cells. FMRFamide alone produced no changes on either the membrane potential or light responses of horizontal cells, but it did suppress the effects of GnRH on horizontal cells in some experiments. FRMFamide also reversed the effects of prolonged darkness on horizontal cell responses. When bicuculline was applied to the retina, horizontal cells also depolarized (approximately 10 mV), responses to full-field illumination decreased, and responses to small spots increased. Most of the effects of bicuculline were suppressed by haloperidol, indicating that bicuculline also stimulates the release of dopamine from interplexiform cells. Similar results were obtained when [D-Ala2]-met-enkephalinamide was applied to the retina; horizontal cells depolarized (approximately 10 mV), responses to full-field stimuli decreased, and responses to the light spots increased. On the other hand, [D-Ala2]-leuenkephalinamide and [D-Ala2, D-Leu5]-enkephalin had no effects on horizontal cells. Both haloperidol and naloxone blocked the effects of [D-Ala2]-met-enkephalinamide on horizontal cells, indicating that [D-Ala2]-met-enkephalinamide stimulates dopamine release from interplexiform cells via specific opiate receptors.