Pain is a major symptom in many medical conditions, and often interferes significantly with a person’s quality of life. Although a priority topic in medical research for many years, there are still few analgesic drugs approved for clinical use. One reason is the lack of appropriate animal models that faithfully represent relevant hallmarks associated with human pain. Here we propose zebrafish (Danio rerio) as a novel short-term behavioral model of nociception, and analyse its sensitivity and robustness. Firstly, we injected two different doses of acetic acid as the noxious stimulus. We studied individual locomotor responses of fish to a threshold level of nociception using two recording systems: a video tracking system and an electric biosensor (the MOBS system). We showed that an injection dose of 10% acetic acid resulted in a change in behavior that could be used to study nociception. Secondly, we validated our behavioral model by investigating the effect of the analgesic morphine. In time-course studies, first we looked at the dose-response relationship of morphine and then tested whether the effect of morphine could be modulated by naloxone, an opioid antagonist. Our results suggest that a change in behavioral responses of zebrafish to acetic acid is a reasonable model to test analgesics. The response scales with stimulus intensity, is attenuated by morphine, and the analgesic effect of morphine is blocked with naloxone. The change in behavior of zebrafish associated with the noxious stimulus can be monitored with an electric biosensor that measures changes in water impedance. Full article

In many animal species, as well as in humans, high doses of fentanyl (F) produce marked neurotoxic effects, such as muscular rigidity and respiratory depression. The antinociception (hot-plate test), impairment of motor coordination (rotarod test) and acute toxicity of intraperitoneal newly synthesized analogs, (±)cis-3-carbomethoxy- fentanyl (C) and (±)trans-3-carbomethoxyfentanyl (T) were evaluated in mice. The compounds tested induced antinociception, impairment of performance on the rotarod, and lethality in a dose-dependent manner. The relative order of antinociceptive potency was similar to motor impairment potency, as well as lethality: F > C > T. Naloxone hydrochloride (1 mg/kg; sc) abolished all the effects observed, suggesting that they are mediated via opioid receptors, most probably of m type. There were no significant differences between the therapeutic indices of F, C and T. It is concluded, the introduction of 3-carbomethoxy group in the piperidine ring of the fentanyl skeleton reduced the potency, but did not affect tolerability and safety of the compound. Full article

Rats were trained for multiple sessions in a place-conditioning shuttle-box to explore motivational interactions of mu and kappa opioid agonists, specifically fentanyl reward and spiradoline aversion. In Phase 1, groups of rats received various doses of mu or kappa agonists, or placebo, testing for preference or aversion. Group A always received saline SC before 15-minute sessions. Group B received fentanyl SC (0.003, 0.006, 0.012 mg/kg), Group C received low and medium doses of agonists SC, and Group D received spiradoline (0.3, 0.6, 1.2 mg/kg) SC during Training Sessions 1-4, rats being restricted to the drug-associated compartment. Rats received saline when restricted to the placebo-associate compartment and on test days with access to both shuttle-box compartments. In Phase 2 of the study, Training Session 5, Combinations of mu and kappa agonists were substituted in Groups B, C, and D. Dose-related preference to fentanyl and aversion to spiradoline occurred during Test Sessions 1-4. During Test Session 5, fentanyl preference in Group B was suppressed by spiradoline, rats in Group C had a saline-like response to combined agonists, and spiradoline aversion in Group D was attenuated by fentanyl. These findings suggest that combined doses of mu and kappa agonists, while additive for antinociception, offset the rewarding and punishing effects of each other. Full article

Opioid compounds and G-protein coupled opioid receptors (ORs) have been studied widely in terms of central nervous system (CNS) actions relating to pain management and drug abuse. Opioids are also linked to induction of mammalian hibernation, a natural state of tolerance involving prolonged and orchestrated shifts in cellular metabolism, growth and stress resistance. It is not surprising then that OR agonism induces acute or delayed cytoprotective states in myocardium, rendering ORs an attractive target for protection of cardiac tissue from the potentially fatal consequences of ischemic heart disease. Cardiac ORs are implicated in triggering/mediating so-called ‘conditioning’ responses, in which powerful cytoprotection arises following transient receptor ligation prior to or immediately following ischemic insult. These responses involve one or more OR sub-types engaging pro-survival kinase cascades to ultimately modulate cell stress and mitochondrial end-effectors. However, important questions remain regarding the role of endogenous opioids, OR signalling, and the transduction and mediation of these protective responses. We briefly review opioid-mediated cardioprotection, focussing on recent developments in signal transduction, the role of receptor ‘cross-talk’, and the effects of sustained OR ligand activation. Full article

Self-injurious behavior (SIB) is a primary reason that individuals with neurodevelopmental disabilities (NDD) are either retained in restrictive environments or are administered psychotropic medication. There are no known causes and no universally accepted treatments for this complex behavior among individuals with NDD. There is developing evidence, however, that individuals exhibiting SIB have a disturbance of the opiate-mediated pain and pleasure system. One hypothesis is that SIB reflects insensitivity to pain and general sensory depression (hypoalgesia), perhaps related to chronic elevation of endogenous opiates. For instance, many self-injurious individuals do not exhibit the usual signs of pain after their “injurious” behavior. Moreover, for some individuals the addictive properties of elevated endogenous opiates (euphoria) may be responsible for maintaining their SIB. In this perspective, SIB may be viewed as an addiction because it supplies the "fix" for tolerant, down-regulated opiate receptors. Reports that levels of endogenous opiates at rest and after SIB episodes predict positive responses to opiate blockers (e.g., naltrexone) provide further support for opiate-mediated SIB and form the basis for a rational treatment strategy. Although the long term effects of opiate blockers on SIB are unknown, reduction in SIB following acute treatment provides support that a specific biological system may be dysregulated in a subgroup of patients. It is concluded that naltrexone produces a clinically significant reduction in the serious and life-threatening behavior of self injury for individuals who have not been responsive to any other type of treatment. Several suggestions and cautions are provided for regimens of naltrexone treatment of SIB. Full article

Opioids inhibit glutamatergic excitatory transmission from the periphery by activating G-protein coupled opioid receptors in the central terminals of primary-afferent neurons in the spinal substantia gelatinosa, resulting in antinociception. Opioid receptor activation in the peripheral terminals of primary-afferent neurons inhibits the production of action potentials in response to nociceptive stimuli given to the periphery, leading to antinociception. Opioids also exhibit a local anesthetic effect without opioid receptor activation in peripheral nerve fibers. This review article will focus on analgesia and anesthesia produced by the actions of opioids on primary-afferent fibers. Full article

This review focuses on the physiological roles for kappa opioid receptors (KORs) in adult animals and humans, as well as in the developing newborn animal. Our recent findings have provided new information that under physiological conditions in conscious newborn animals, activation of KORs with the selective agonist, U-50488H, results in an aquaresis, as previously observed in adult animals and humans. In addition, we have shown in conscious lambs that KORs modulate systemic and renal haemodynamics as well as the arterial baroreflex control of heart rate, providing a previously unidentified role for KORs. Full article