Non-addictive orally-active kappa opioid agonists for the treatment of peripheral pain in rats.

Addiction to conventional opioid pain analgesics is a major societal problem that is increasing at an alarming rate. New drugs to combat the effects of opioid abuse are desperately needed. Kappa-opioid agonists are efficacious in peripheral pain models but suffer from centrally-mediated effects. In this article, we discuss our efforts in developing peripheral kappa-based opioid receptor agonists that have the potential analgesic activity of opioids but do not manifest the negative side-effects of opioid use and abuse. Further, derivatives of the tetra-peptide D-Phe-D-Phe-D-Nle-D-Arg-NH2, such as CR665, exhibit high peripheral to central selectivity in analgesic models when administered intravenously (i.v.); however, they are inactive when administered orally. Application of our laboratory's proprietary non-natural amino acid technology to CR665 produced derivatives that exhibit peripheral analgesic activity when dosed orally but do not promote CNS-based effects. Lead compound JT09 activates the kappa-opioid receptor with EC50s in the low nM range, while agonist selectivity for kappa over other peripheral opioid receptors was >33,400 fold. Results indicate that JT09 is approximately as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated activity. Additionally, JT09 did not promote other CNS-mediated effects associated with morphine (addiction, sedation, dysphoria, tolerance, addiction). Thus, we propose that JT09 has potential for development as a novel analgesic. PERSPECTIVE: This article presents data supporting the analgesic properties of an orally available, peripherally-restricted, kappa-opioid agonist for peripheral pain. A potential out-patient pharmaceutical that acts as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated effects, could help reduce the current health care burden associated with prescription opioids.

Reflexiones sobre la neurotoxicidad inducida por opioides en el contexto de una anestesia general en población pediátrica / Opioid related neurotoxicity on pediatric population after general anestesia

Introducción: Desde el año 2000 vienen apareciendo en distintas publicaciones científicas los resultados de numerosos estudios experimentales realizados en animales, evaluando el impacto neurotóxico que sobre sus cerebros tenía la exposición a combinaciones de anestésicos de uso habitual. Se constata que la exposición en periodo de máxima sinaptogénesis conlleva una apoptosis neural diseminada. Comienzan entonces a preocuparse los anestesiólogos que trabajan con niños, pues quizás ese daño neuronal también pudiera acontecer a la población pediátrica. Así, son varios los estudios que están en marcha desde hace años valorando el desarrollo neurocognitivo de cohortes de niños que se sometieron a anestesias generales en edades tempranas de sus vidas. En este sentido, la necesidad de medir un daño cerebral agudo nos anima a utilizar marcadores que han demostrado su asociación con dicho deterioro cerebral en diferentes situaciones clínicas como la hipoxia perinatal, la parada cardiorrespiratoria o el traumatismo craneoencefálico. Objetivos: Planteamos este trabajo con el objetivo de determinar si la proteína S100B podría comportarse como un biomarcador de daño cerebral agudo postanestésico y si pudiéramos establecer asociación entre la elevación de este marcador en sangre y alguno de los fármacos anestésicos utilizados habitualmente. Metodología: Determinación sanguínea de la proteína S100B en 76 pacientes pediátricos intervenidos de hipertrofia amigdalar bajo anestesia general, antes y después de la cirugía Conclusión: Tras analizar los resultados podemos concluir que existe una elevación estadísticamente significativa entre los niveles de proteína S100B antes y después de la exposición anestésica. En segundo lugar, podemos establecer una correlación positiva, también con significación estadística, entre el fentanilo administrado y la elevación de dicha proteína al final del acto anestésico (AU)

Introduction: In the last decade many scietific publications bring out the results of experimental studies about the neurotoxic impact of an anesthetic expossure in animal´s brain. It is confirm that when this expossure occurs in a maximum synaptogenesis period of the animal´s live a widespread neuroapoptosis befall. From there on all the pediatrics anesthesiologist warried about if this damage could also affect the pediatric population. Nowadays there are several observational studies exploring the neurobehavioral conduct of many children who underwent general anesthesia early in their lives. Objetive: As a results of this we propose to use actual neuronal damage biomarkes, wich have demonstrated association between brain damage and perinatal hypoxia, or cardiac arrest or mild brain injury. When we planned this essay we intend to determine if S100B protein could work as an accute postanesthetic expossure neuronal damage biomarker, and if there would be any relationship between the biomarker elevation and any of the drugs commonly use for anesthesia. Metodology: In order to determinate the S100B protein serum level is, we obtained a blood sample before and after general anaesthesia expousure in 76 paediatric patient undergoing amigdalar hypertropy surgery. Conclusions: Once we analized our results we can coclude that an elevation of the blood levels of S100B protein occurs after anesthesia. We have also found a possitive correlation between the total amount of fentanyl administred and the higher level of this protein concentration at the end of the anesthetic expossure (AU)

Striatal patch compartment lesions reduce stereotypy following repeated cocaine administration.

Stereotypy can be characterized as inflexible, repetitive behaviors that occur following repeated exposure to psychostimulants, such as cocaine (COC). Stereotypy may be related to preferential activation of the patch (striosome) compartment of striatum, as enhanced relative activation of the patch compartment has been shown to positively correlate with the emergence of stereotypy following repeated psychostimulant treatment. However, the specific contribution of the patch compartment to COC-induced stereotypy following repeated exposure is unknown. To elucidate the involvement of the patch compartment to the development of stereotypy following repeated COC exposure, we determined if destruction of this sub-region altered COC-induced behaviors. The neurons of the patch compartment were ablated by bilateral infusion of the neurotoxin dermorphin-saporin (DERM-SAP; 17 ng/µl) into the striatum. Animals were allowed to recover for eight days following the infusion, and then were given daily injections of COC (25mg/kg) or saline for one week, followed by a weeklong drug-free period. Animals were then given a challenge dose of saline or COC, observed for 2h in activity chambers and sacrificed. The number of mu-labeled patches in the striatum were reduced by DERM-SAP pretreatment. In COC-treated animals DERM-SAP pretreatment significantly reduced the immobilization and intensity of stereotypy but increased locomotor activity. DERM-SAP pretreatment attenuated COC-induced c-Fos expression in the patch compartment, while enhancing COC-induced c-Fos expression in the matrix compartment. These data indicate that the patch compartment contributes to repetitive behavior and suggests that alterations in activity in the patch vs matrix compartments may underlie to this phenomenon.

Brainstem opioidergic system is involved in early response to experimental SAH.

Subarachnoid hemorrhage (SAH) is a form of stroke with high rates of mortality and permanent disability for patients who survive the initial event. Previous research has focused on delayed cerebral vasospasm of large conduit arteries as the cause of poor long-term outcomes after SAH. New evidence suggests that acute failure to restore cerebral blood flow (CBF) after SAH may be setting the stage for delayed ischemic neurological deficits. Our lab previously demonstrated that the rostral ventromedial medulla (RVM), an autonomic and sensorimotor integration center, is important for maintaining CBF after experimental SAH. In this study, we have demonstrated that ablation of µ-opioid receptor containing cells with dermorphin conjugates in the RVM results in a high mortality rate after experimental SAH and, in survivors, causes a dramatic decrease in CBF. Further, locally blocking the µ-opioid receptor with the antagonist naltrexone attenuated the reduction in CBF secondary to experimental SAH. Saturating µ-opioid receptors with the agonist [D-Ala(2),NMe-Phe(4),Gly-ol(5)]-encephalin (DAMGO) had no effect. Taken together, these results suggest that SAH activates opioidergic signaling in the RVM with a resultant reduction in CBF. Further, cells in the RVM that contain µ-opioid receptors are important for survival after acute SAH. We propose that failure of the RVM µ-opioid receptor cells to initiate the compensatory CBF response sets the stage for acute and delayed ischemic injury following SAH.

Striatal patch compartment lesions alter methamphetamine-induced behavior and immediate early gene expression in the striatum, substantia nigra and frontal cortex.

Methamphetamine (METH) induces stereotypy, which is characterized as inflexible, repetitive behavior. Enhanced activation of the patch compartment of the striatum has been correlated with stereotypy, suggesting that stereotypy may be related to preferential activation of this region. However, the specific contribution of the patch compartment to METH-induced stereotypy is not clear. To elucidate the involvement of the patch compartment to the development of METH-induced stereotypy, we determined if destruction of this sub-region altered METH-induced behaviors. Animals were bilaterally infused in the striatum with the neurotoxin dermorphin-saporin (DERM-SAP; 17 ng/µl) to specifically ablate the neurons of the patch compartment. Eight days later, animals were treated with METH (7.5 mg/kg), placed in activity chambers, observed for 2 h and killed. DERM-SAP pretreatment significantly reduced the number and total area of mu-labeled patches in the striatum. DERM-SAP pretreatment significantly reduced the intensity of METH-induced stereotypy and the spatial immobility typically observed with METH-induced stereotypy. In support of this observation, DERM-SAP pretreatment also significantly increased locomotor activity in METH-treated animals. In the striatum, DERM-SAP pretreatment attenuated METH-induced c-Fos expression in the patch compartment, while enhancing METH-induced c-Fos expression in the matrix compartment. DERM-SAP pretreatment followed by METH administration augmented c-Fos expression in the SNpc and reduced METH-induced c-Fos expression in the SNpr. In the medial prefrontal, but not sensorimotor cortex, c-Fos and zif/268 expression was increased following METH treatment in animals pre-treated with DERM-SAP. These data indicate that the patch compartment is necessary for the expression of repetitive behaviors and suggests that alterations in activity in the basal ganglia may contribute to this phenomenon.

Un caso de cefalea post traumática: consideraciones sobre clasificación, fisiopatología y tratamiento / A case of post-traumatic headache: classification, pathophysiology and treatment

Paciente mujer de 35 años con diagnóstico de cefalea post traumática (CPT) y debut de clínica 3 años antes tras una caída complicada con parada cardiaca. Policontusiones en región frontotemporal derecha. Precisó soporte ventilatorio durante 11 días. Al alta cefalea tensional continua, bilateral. Se le practicaron bloqueos diagnósticos de ramo mediano de facetas cervicales y bloqueos de nervio occipital mayor sin experimentar alivio alguno. Posteriormente se procedió a bloqueo de ganglio estrellado (BGE) en lado derecho en C7 con alivio total de dolor en la parte derecha de la cabeza. La cefalea es el síntoma más prevalente del síndrome post traumático. Se definen los criterios diagnósticos para CPT crónica atribuida a traumatismo moderado. La fisiopatología del dolor en la CPT es poco conocida. Los nuevos avances en técnica de neuroimagen y estudios experimentales han abierto las puertas a conceptos novedosos que podrían explicar el mecanismo del dolor. En pacientes con CPT se ha supuesto un mecanismo fisiopatológico por medio de sensibilización central y periférica, además de una vía común del dolor a través del relé cérvico trigeminal. En un traumatismo craneal las vías del dolor pueden verse dañadas en uno o varios niveles: consecuentemente uno o varios tipos de dolor pueden coexistir. El efecto del bloqueo del ganglio estrellado supone la denervación temporal de todas las fibras simpáticas de cabeza y cuello. Si la CPT compartiera con las cefaleas primarias los mecanismos de sensibilización periférica y la alteración de la vasoregulación cerebral, se explicarían los efectos analgésicos del bloqueo del simpático cérvico torácico. El efecto inesperado del BGE sobre la CPT nos hace pensar que la International Classification of Headache Disorders II tendría que revisarse. El BGE debería tenerse en cuenta como herramienta diagnóstico terapéutica en caso de cefaleas refractarias (AU)

Case report of a 35 year old woman with a post traumatic headache (PTH). Onset of the pain three years earlier, after falling on the ground, which required resuscitation. She had to be on mechanical ventilation for 11 days and suffered several contusions on the right frontal-temporal area of the skull. On discharge, she complained of a continuous bilateral tension headache; she underwent diagnostic cervical medial branch blocks and bilateral mayor occipital nerve blocks with no findings. Subsequently, a C7 stellate ganglion block (SGB) on the right side was performed with full pain relief on the same side. Headache is the most prevalent symptom of post concussion syndrome. Diagnostic criteria for chronic PTH secondary to moderate traumatic brain injury are described in the discussion. The pathophysiology of PTH is poorly understood. Neuroimaging and experimental models offer novel theories to explain a common mechanism for pain in PTH and primary headaches. It is assumed that a central and a peripheral sensitization may act through a common pain pathway such as the cervico-trigeminal relay. After a brain injury, pain pathways may be damaged at different levels, causing different types of pain. A clinical case is described here, in which pharmacotherapy, cervical medial branch blocks and occipital nerve blocks failed. On the other hand, SGB was effective, the reason for which might be found in the pathophysiology of the PTH, as it causes a temporary block of all the sympathetic fibres to the head and neck. If PTH shared the peripheral sensitization mechanism and the vasoregulation impairment with primary headaches, analgesic properties from cervicothoracic sympathetic block would be explained. This unexpected effect should stimulate a review of the International Classification of Headache Disorders II. Stellate ganglion block should be considered as a diagnostic and therapeutic option in case of resistant headache (AU)

Evaluation of side effects through selective ablation of the mu opioid receptor expressing descending nociceptive facilitatory neurons in the rostral ventromedial medulla with dermorphin-saporin.

Descending facilitation from the rostral ventromedial medulla (RVM) contributes to some pathological pain states. The intra-RVM microinjection with dermorphin-saporin could specifically abolish this facilitation in rodent models by selectively ablating the RVM neurons expressing mu opioid receptors. Thus, this targeted lesion may be an alternative mechanism-based approach for intractable pain. This research was performed to investigate potential side effects after a single intra-RVM application of dermorphin-saporin in rats. Results showed though some acute cardiovascular signs were observed with dermorphin-saporin, the treatment exhibited no long-lasting significant influence on some physiological functions for up to 3-month observation period, including normal sensory function, locomotor activity, ingestive behaviors, body weight, rectal temperature, respiratory rate, heart rate, systolic blood pressure, cardiac structure and function. Moreover, there were only mild microglial responses on day 7 post-microinjection, while no significant increase in the immunostaining of astrocytes and no noticeable up-regulation in the production of proinflammatory cytokines were detected in the RVM treated with dermorphin-saporin. Taken together, these data would suggest that this selective ablation of mu opioid receptor bearing descending facilitatory neurons in the RVM with dermorphin-saporin did not elicit the long-standing evident adverse toxicity in terms of some physiological parameters and neurochemical alterations we determined, plausibly providing us a safe and reliable approach to treat some intractable pain.

Study of the cytotoxicity and antioxidant capacity of N/OFQ(1-13)NH2 and its structural analogues.

The effect of side-chain shortening of N/OFQ(1-13)NH(2) at position 9 ([Orn(9)]N/OFQ(1-13)NH(2), [Dab(9)]N/OFQ(1-13)NH(2), [Dap(9)]N/OFQ(1-13)NH(2)) was studied regarding potential toxicity and antioxidant capacity. Staurosporine- and H2O2-induced damage of SH-SY5Y neuroblastoma cells was not changed in the presence of N/OFQ(1-13)NH(2) and [Orn(9)]N/OFQ(1-13)NH(2), but was strongly enhanced in the presence of [Dab(9)]N/OFQ(1-13)NH(2) and [Dap(9)]N/OFQ(1-13)NH(2). Moreover, treatment of cells with the latter two analogues alone led to cell injury. Neuropeptide-dependent differences in the viability of SH-SY5Y cells were also observed, i.e., a cytoprotective effect was observed only in the presence of N/OFQ(1-13)NH(2) and [Orn(9)]N/OFQ(1-13)NH(2). Compared to [Dab(9)]N/OFQ(1-13)NH(2) and [Dap(9)]N/OFQ(1-13)NH(2), the effects of N/OFQ(1-13)NH(2) and [Orn(9)]N/OFQ(1-13)NH(2) were more beneficial in systems generating free oxygen radicals (O(2)(-) and .OH), as well as on the antioxidant status of rat brain and liver. Taken together, our findings show that N/OFQ(1-13)NH(2) and its structural analogue [Orn(9)]N/OFQ(1-13)NH(2) possess more favorable profiles than the other two nociceptin (N/OFQ) analogues. The present results suggest that shortening of the side-chain of N/OFQ(1-13)NH(2) might increase cell damage and reduce the viability of SH-SY5Y neuroblastoma cells. Moreover, such alterations may lead to changes in free-oxygen generating systems and in antioxidant status in animal tissues.

Sex differences in micro-opioid receptor expression in the rat midbrain periaqueductal gray are essential for eliciting sex differences in morphine analgesia.

Opioid-based narcotics are the most widely prescribed therapeutic agent for the alleviation of persistent pain; however, it is becoming increasingly clear that morphine is significantly less potent in women compared with men. Morphine primarily binds to mu-opioid receptors (MORs), and the periaqueductal gray (PAG) contains a dense population of MOR-expressing neurons. Via its descending projections to the rostral ventromedial medulla and the dorsal horn of the spinal cord, the PAG is considered an essential neural substrate for opioid-based analgesia. We hypothesized that MOR expression in the PAG was sexually dimorphic, and that these sex differences contribute to the observed sex differences in morphine potency. Using immunohistochemistry, we report that males had a significantly higher expression of MOR in the ventrolateral PAG compared with cycling females, whereas the lowest level of expression was observed in proestrus females. CFA-induced inflammatory pain produced thermal hyperalgesia in both males and females that was significantly reversed in males with a microinjection of morphine into the ventrolateral PAG; this effect was significantly greater than that observed in proestrus and estrus females. Selective lesions of MOR-expressing neurons in the ventrolateral PAG resulted in a significant reduction in the effects of systemic morphine in males only, and this reduction was positively correlated with the level of MOR expression in the ventrolateral PAG. Together, these results provide a mechanism for sex differences in morphine potency.

Muerte por sobredosis: de la reacción aguda tras consumo de opiáceos a la muerte asociada al policonsumo / Fatal Overdose: from opiate acute reaction to polydrug-related death

El consumo de drogas de abuso es una de las causas más importantes de muerte entre jóvenes de la Unión Europea, bien sea por SIDA o reacción aguda al consumo de las mismas. El registro de la mortalidad es un indicador de prevalencia del consumo de drogas, siendo implantado en nuestro país en el año 1987 por el SEIT, y que desde la creación del Observatorio Europeo de la droga y toxicomanías, permite la comparación de la información obtenida de los distintos países de la UE. En los diez últimos años el número total de muertes anuales por RAD registrado oscila entre 7000 y 9000, con tendencias que varían según el país, aunque en general se puede decir que se aprecia una estabilización de la prevalencia del consumo problemático de drogas en algunos países, a la vez que disminuye el consumo por vía parenteral. La ratio de mortalidad anual por sobredosis de opiáceos se sitúa hoy en día entre el 1 y el 3%, producida por diferentes mecanismos, siendo el más importante el policonsumo de drogas, particularmente depresores del SNC como el alcohol o las benzodiacepinas. Los hombres de mediana edad representan la mayoría de las víctimas de sobredosis, no encontrándose diferencias significativas en los días de la semana en que se producen. Según datos del Observatorio Europeo las muertes causadas por sobredosis de cocaína o éxtasis, sin intervención de los opiáceos, son poco frecuentes en Europa, aunque existe una clara tendencia al alza. La presencia de metadona en fluidos biológicos del fallecido es significativa en los últimos años, pero se cree más probable que la muerte esté más relacionada con el consumo de metadona ilegal y no prescrita en un centro terapéutico, de hecho se ha demostrado que el tratamiento con esta sustancia reduce hasta un75 % la mortalidad asociada a sobredosis de opiáceos (AU)

Drugs consumption is one of the main causes of death in young people from the European Union, either by an acute reaction to their consumption or because of AIDS. Mortality rates register is a prevalence indicator of drugs consumption, being introduced in our country in 1987 by the SEIT, and from the establishment of the European Observatory for drugs and addictions it allows comparison between the information obtained from European Union different countries.In the last ten years the total number of deaths per year by RAD ranges between 7000 and 9000, with trends differences between countries, although generally it can be said that a stabilization in the prevalence of problematic consumption is observed in some countries, along with a decrease in endovenous consumption. Mortality per year rate as a result of opiates overdoses is nowadays between 1 and 3%, and is caused by different mechanisms, being the main of them (drugs policonsumption?) (the consumption of several drugs), specially when includes SNC depressors as alcohol or benzodiazepines. Medium age men represent most of the overdoses victims, without significant differences on the day of the week in which occurs. According to European Observatory data, deaths caused by cocaine or extasis overdoses, without simultaneous opiates consumption, are not common in Europe, although there is a clear rising trend. In last years the presence of methadone in biological fluids of the deceased is significant, but probably death is more related to consumption of methadone not prescribed in a therapeutic setting or illegal; in fact, treatment with this substance has proved to diminish up to 75% the mortality associated with opiates overdoses (AU)

Involvement of the histaminergic system in the nociceptin-induced pain-related behaviors in the mouse spinal cord.

Intrathecal (i.t.) injection of nociceptin elicited a behavioral response mainly consisting of biting and licking, which were eliminated by the i.t. co-administration of opioid receptor-like-1 (ORL-1) receptor antagonists. The behavioral response induced by nociceptin was characteristically similar to that by i.t.-administered histamine, and was attenuated by i.t. co-administration of the H1 receptor antagonists, but not by the H2 receptor antagonists, whereas the H3 receptor antagonist promoted the nociceptin-induced behavior. H1 receptor knockout (H1R-KO) mice did not show the nociceptin-induced nociceptive behavior, which was observed in wild-type mice. Pretreatment with a histamine antiserum or a histidine decarboxylase inhibitor resulted in a significant reduction of the response to nociceptin. The previous studies showed that NK1 receptor antagonists and a novel substance P (SP)-specific antagonist given i.t. could reduce the behavioral response to nociceptin and histamine. On the other hand, the nociceptive response induced by nociceptin, but not histamine, was completely attenuated by the i.t. co-administration of agonists for GABAA and GABAB receptors. In contrast, the antagonists for GABAA and GABAB receptors injected i.t. showed same nociceptive response with nociceptin and histamine, and their nociceptive responses were significantly blocked by the i.t. co-administration of the H1 receptor antagonists, but not H2 receptor antagonists or ORL-1 receptor antagonists. The present results suggest that the activation of the ORL-1 receptor by nociceptin may induce the disinhibition of histaminergic neuron and enhance the release of histamine, which subsequently acts on the H1 receptor located on the SP-containing neurons to produce the spinal cord-mediated nociceptive response.

Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain.

Intracerebral administration of the excitotoxin ibotenate to newborn mice induces white-matter lesions, mimicking brain lesions that occur in human preterm infants. Nociceptin (NC), also called orphanin FQ, is the endogenous ligand of the opioid receptor-like 1 (ORL1) receptor and does not bind classical high-affinity opioid receptors. In the present study, administration of NC exacerbated ibotenate-induced white-matter lesions while coadministration of ibotenate with either of two NC antagonists reduced excitotoxic white-matter lesions by up to 64%. Neither ibotenate plus endomorphin I (a selective mu receptor agonist), nor ibotenate plus naloxone (a classical opioid receptor antagonist) modulated the excitotoxic lesion. Pretreatment with antisense oligonucleotides targeting the NC precursor peptide mRNA significantly reduced ibotenate-induced white-matter damage. Finally, high doses of fentanyl, which stimulates both classical mu-opioid receptors and ORL1, exacerbated excitotoxic white-matter lesion. This toxic effect was blocked by inhibiting ORL1 but not classical opioid receptors. Together, these findings show that endogenous or exogenous stimulation of the ORL1 receptor can be neurotoxic and that blocking NC signaling protects the white matter against excitotoxic challenge. These data point to potential new avenues for neuroprotection in human preterm infants at high risk of brain lesions.

Effects of nocistatin on nociceptin-induced impairment of learning and memory in mice.

We investigated the effects of nociceptin/orphanin FQ and nocistatin on learning and memory function as measured in a step-down type passive avoidance task and spontaneous alternation of Y-maze with mice. Nociceptin (0.5-5.0 nmol/mouse, i.c.v.) 30 min before the training session or Y-maze test, dose dependently shortened the step-down latency and impaired spontaneous alternation, while there was no significant effect of nocistatin (0.5-5.0 nmol/mouse). Interestingly, nocistatin (5.0 nmol) significantly improved the nociceptin (5.0 nmol)-induced impairment of learning and memory without changing motor activity or response to electric shocks. These results suggest that nocistatin, a new biologically active peptide now found to also counteract the impairment of learning and memory induced by nociceptin, plays an important role in the regulation of learning and memory process in the central nervous system.

Orphan opioid receptor antisense probes block orphanin FQ-induced hyperphagia.

Orphanin FQ/nociceptin binds with high affinity to the orphan opioid receptor-like/K-3 (ORL1/KOR-3) clone, and stimulates feeding. The present study demonstrated that antisense oligodeoxynucleotides directed against either exons 1, 2 or 3 of the ORL1/KOR-3 clone reduced orphanin FQ/nociceptin-induced hyperphagia. A missense probe was ineffective. Naltrexone dose-dependently reduced orphanin FQ/nociceptin-induced hyperphagia. These data suggest that the receptor responsible for orphanin FQ/nociceptin-induced hyperphagia is encoded by the ORL1/KOR-3 clone.

Neurotoxic versus neuroprotective actions of endogenous opioid peptides: implications for treatment of CNS injury.

Endogenous opioid systems seem to have both neurodestructive and neuroprotective roles in CNS injury. Whereas mu and kappa 1 receptors appear to mediate neuroprotective actions, kappa 2 receptors may be involved in secondary injury responses. Among the endogenous opioids, dynorphin has marked neurotoxic effects when given intrathecally to rats; when administered in subinjury doses, dynorphin exacerbates the response to brain or spinal cord trauma. Because of the neurotoxic effects of dynorphin, one should employ this compound with great caution in human studies of addiction treatment. It has not been established which endogenous opioids might be protective. Taken together, these observations may suggest novel approaches to the treatment of CNS injury using selective mixed opioid agonist-antagonist compounds such as buprenorphine.