Levels Of Dynorphin Research Articles

Involvement of kappa/dynorphin system in the development of tolerance to nicotine‐induced antinociception

The aim of the present study was to explore the possible role of kappa/dynorphin system in the development of tolerance to nicotine antinociception in mice. First, we observed that kappa-opioid receptor (KOP-r) participates in the acute spinal antinociception produced by nicotine (3 and 5 mg/kg, s.c.) since the pre-treatment with the selective kappa antagonist nor-binaltorphimine (3 mg/kg, i.p.) attenuated this response in the tail-immersion test but not in the hot-plate test nor in locomotor responses. Possible changes in the expression of KOP-r were investigated in tolerant mice to nicotine antinociception by using autoradiography of [3H]CI-977 binding. The density of KOP-r decreased in the spinal cord of tolerant mice. In addition, bi-directional cross-tolerance between nicotine (3 and 5 mg/kg, s.c.) and the selective kappa agonist U50,488H (10 mg/kg, s.c.) was found in the tail-immersion test. Recent evidences indicate that an up-regulation of dynorphin levels in the spinal cord and subsequent activation of NMDA receptors participate in the development of tolerance to opioid and cannabinoid antinociception. In this study, dynorphin content in the lumbar spinal cord was similar in control and nicotine tolerant mice. Furthermore, the administration of the NMDA antagonist MK-801 (0.03 and 0.01 mg/kg, i.p.) before each daily nicotine injection did not modify the development of nicotine tolerance. In summary, these data indicate that KOP-r is directly involved in the development of tolerance to nicotine antinociception by a mechanism independent from dynorphin and NMDA receptors.

Can’t Get Enough of That Dopamine

Can’t Get Enough of That Dopamine

Opioid, cheating on its receptors, exacerbates pain

Opioids are commonly thought of as compounds that alleviate pain. A new study finds that elevated levels of the opioid dynorphin can unexpectedly activate bradykinin receptors, contributing to the maintenance of neuropathic pain.

??-Opioid Receptor Antagonism Improves Recovery from Myocardial Stunning in Chronically Instrumented Dogs

We tested the hypothesis that the selective kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) improves recovery from myocardial stunning. Ten dogs were chronically instrumented for measurement of heart rate, left atrial, aortic and left ventricular pressure (LVP), and the maximum rate of LVP increase (LV dP/dt(max)) and decrease (LV dP/dt(max)), coronary blood flow velocity and myocardial wall-thickening fraction. Regional myocardial blood flow was determined with fluorescent microspheres. Catecholamine plasma levels were measured by high-performance liquid chromatography, and beta-endorphin and dynorphin plasma levels by radioimmunoassay. An occluder around the left anterior descending artery (LAD) allowed induction of a reversible LAD-ischemia. Animals underwent two experiments in a randomized crossover fashion on separate days: (a) 10 min LAD-occlusion (control experiment), (b) second ischemic episode 24 h after nor-BNI (2.5 mg/kg IV) (intervention). Dogs receiving nor-BNI showed an increase in wall-thickening fraction, LV dP/dt(max) and LV dP/dt(min) before ischemia and during the whole reperfusion (P < 0.05 versus control experiment). After nor-BNI pretreatment, dynorphin levels increased after induction of ischemia to a peak level of 15.1 +/- 3.6 pg/mL (P < 0.05 versus control experiment). The increase in plasma beta-endorphin during ischemia and early reperfusion was attenuated after nor-BNI. Compared with the control experiment, nor-BNI left global hemodynamics, regional myocardial blood flow, and catecholamine levels unchanged. In conclusion, nor-BNI improves recovery from myocardial stunning after regional myocardial ischemia in chronically instrumented dogs.

κ-Opioid Receptors Mediate Cardioprotection by Remote Preconditioning

Remote preconditioning is known to be cardioprotective, but the exact mechanism has not been fully elucidated. The objective of the current study was to investigate the role of kappa-opioid receptors in cardioprotection by remote preconditioning and reveal possible underlying mechanisms. Remote preconditioning was induced in anesthetized male Sprague-Dawley rats by three cycles of 5 min of right femoral artery occlusion followed by 5 min of reperfusion. Myocardial ischemia-reperfusion was achieved by ligation of the left anterior descending coronary artery for 30 min and then reperfusion for 120 min. Infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining. Levels of lactate dehydrogenase, dynorphin, and met-enkephalin in plasma were measured. The opening of the mitochondrial permeability transition pore was monitored with fluorescent calcein in isolated ventricular myocytes. Both remote preconditioning and U-50,488H (10 mg/kg intravenous), a kappa-opioid receptor agonist, significantly decreased the infarct size and plasma lactate dehydrogenase level induced by ischemia-reperfusion, and these effects were attenuated by nor-binaltorphimine (10 mg/kg intravenous), a kappa-opioid receptor antagonist, and atractyloside (5 mg/kg intravenous), a mitochondrial permeability transition pore activator. However, administration of naltrindole (5 mg/kg), a delta-opioid receptor antagonist, had no effect on the cardioprotection by remote preconditioning. The dynorphin plasma level was increased after remote preconditioning treatment, but the met-enkephalin level did not change. In isolated ventricular myocytes loaded with calcein, U-50,488H (300 microM) decreased the mitochondrial permeability transition pore opening induced by calcium (200 microM), and this effect was attenuated by cotreatment with nor-binaltorphimine (5 microM) or atractyloside (20 microM). Activation of cardiac kappa-opioid receptors is involved in the cardioprotection induced by remote preconditioning, and the mitochondrial permeability transition pore may participate in the postreceptor pathway.

Nalfurafine, a kappa opioid receptor agonist, inhibits scratching behavior secondary to cholestasis induced by chronic ethynylestradiol injections in rats

Scratching is the behavioral manifestation of pruritus. The pruritus of cholestasis can be severe, intractable and affect the quality of life. We investigated if ethynylestradiol (EE)-induced cholestasis is associated with scratching in rats and if nalfurafine, a kappa opioid receptor agonist with antipruritic effects in human uremic pruritus, would antagonize such scratching. Chronic injection of EE (2 mg/kg, s.c., for 14 days) induced cholestasis as documented by increased serum concentrations of bile acids and caused a higher incidence of body scratching compared to vehicle, thus providing an animal model to study scratching behavior secondary to cholestasis. Pretreating the rats with nalfurafine (0.005–0.04 mg/kg, s.c.) inhibited EE-induced scratching dose-dependently with an A 50 value of 0.013 (0.009–0.021) mg/kg. Serum levels of dynorphin A and nitric oxide were decreased in rats with cholestasis compared to control animals. Our data suggest that (a) nalfurafine has the potential to relieve cholestatic pruritus and (b) both kappa opioid and nitric oxide systems are involved, at least in part, in mediating the pruritus of cholestasis.

Dysregulation of dynorphins in Alzheimer disease

The opioid peptides dynorphins may be involved in pathogenesis of Alzheimer disease (AD) by inducing neurodegeneration or cognitive impairment. To test this hypothesis, the dynorphin system was analyzed in postmortem samples from AD and control subjects, and subjects with Parkinson or cerebro-vascular diseases for comparison. Dynorphin A, dynorphin B and related neuropeptide nociceptin were determined in the Brodmann area 7 by radioimmunoassay. The precursor protein prodynorphin, processing convertase PC2 and the neuroendocrine pro7B2 and 7B2 proteins required for PC2 maturation were analyzed by Western blot. AD subjects displayed robustly elevated levels of dynorphin A and no differences in dynorphin B and nociceptin compared to controls. Subjects with Parkinson or cerebro-vascular diseases did not differ from controls with respect to any of the three peptides. PC2 levels were also increased, whereas, those of prodynorphin and pro7B2/7B2 were not changed in AD. Dynorphin A levels correlated with the neuritic plaque density. These results along with the known non-opioid ability of dynorphin A to induce neurodegeneration suggest a role for this neuropeptide in AD neuropathology.

Alterations in prodynorphin gene expression and dynorphin levels in different brain regions after chronic administration of 14-methoxymetopon and oxycodone-6-oxime

Previous studies showed that opioid drugs—oxycodone-6-oxime and 14-methoxy-5-methyl-dihydromorphinone (14-methoxymetopon)—produced less respiratory depressive effect and slower rate of tolerance and dependence, respectively. It was also reported that morphine decreased the prodynorphin gene expression in the rat hippocampus, striatum and hypothalamus. In this study, we determined the prodynorphin gene expression and dynorphin levels in selected brain regions of opioid tolerant rats. We found that in the striatum morphine decreased, while oxycodone-6-oxime increased and 14-methoxymetopon did not alter the prodynorphin gene expression. In the nucleus accumbens, morphine and oxycodone-6-oxime did not change, while 14-methoxymetopon increased the prodynorphin gene expression. In the hippocampus both oxycodone-6-oxime and 14-methoxymetopon enhanced, whereas morphine did not alter the prodynorphin gene expression. In the rat striatum only oxycodone-6-oxime increased dynorphin levels significantly in accordance with the prodynorphin mRNA changes. In the hippocampus both opioid agonists increased the dynorphin levels significantly similarly to the augmented prodynorphin gene expression. In ventral tegmental area only 14-methoxymetopon increased dynorphin levels significantly. In nucleus accumbens and the temporal-parietal cortex the changes in the prodynorphin gene expression and the dynorphin levels did not correlate. Since the endogenous prodynorphin system may play a modulatory role in the development of opioid tolerance, the elevated supraspinal dynorphin levels appear to be partly responsible for the reduced degree of tolerance induced by the investigated opioids.

A Microdialysis Profile of Dynorphin A1–8 Release in the Rat Nucleus Accumbens Following Alcohol Administration

Pharmacological studies have implicated the endogenous opioid system in mediating alcohol intake. Other evidence has shown that alcohol administration can influence endorphinergic and enkephalinergic activity, while very few studies have examined its effect on dynorphinergic systems. The aim of the present study was to investigate the effect of alcohol administration or a mechanical stressor on extracellular levels of dynorphin A(1-8) in the rat nucleus accumbens-a brain region that plays a significant role in the processes underlying reinforcement and stress. Male Sprague-Dawley rats were implanted with a microdialysis probe aimed at the shell region of the nucleus accumbens. Artificial cerebrospinal fluid was pumped at a rate of 1.5 microL/min in awake and freely moving animals and the dialysate was collected at 30-minute intervals. In one experiment, following a baseline period, rats were injected intraperitoneally with either physiological saline or 1 of 3 doses of alcohol, 0.8, 1.6, or 3.2 g ethanol/kg body weight. In a second experiment, following a baseline period, rats were applied a clothespin to the base of their tail for 20 minutes. The levels of dynorphin A(1-8) in the dialysate were analyzed with solid-phase radioimmunoassay. Relative to saline-treated controls, an alcohol dose of 1.6 and 3.2 g/kg caused a transient increase in the extracellular levels of dynorphin A(1-8) in the first 30 minutes of alcohol administration. However, the effect resulting from the high 3.2 g/kg dose was far more pronounced and more significant than with the moderate dose. There was no effect of tail pinch on dynorphin A(1-8) levels in the nucleus accumbens. In this experiment, a very high dose of alcohol was especially capable of stimulating dynorphin A(1-8) release in the nucleus accumbens. Dynorphin release in the accumbens has been previously associated with aversive stimuli and may thus reflect a system underlying the aversive properties of high-dose alcohol administration. However, the lack of effect of tail-pinch stress in the present study suggests that dynorphin A(1-8) is not released in response to all forms of stressful/aversive stimuli.

Variations in opioid peptide levels during the estrous cycle in Sprague–Dawley rats

The estrous cycle, with its various hormonal conditions, may provide us with the means of understanding how endocrine states relate to opioid mechanisms. There has been increasing experimental support for interaction between sex steroids and opioid peptides in the central nervous system. Here, we describe fluctuations in endogenous brain immunoreactive (ir) peptide levels during various phases of the estrous cycle in the female Sprague-Dawley rat. Ir levels of dynorphin A, dynorphin B, Leu-enkephalin-Arg(6), Met-enkephalin-Arg(6)Phe(7) and nociceptin/orphanin FQ were measured in the pituitary gland and in 10 areas of the brain during the diestrus, proestrus and estrus phase. In several areas of the brain, basal levels of endogenous opioid peptides showed variation during the course of the estrous cycle. Significant differences were found between the diestrus state and the proestrus and/or estrus conditions, particularly in the nucleus accumbens, caudate putamen and the substantia nigra. The ir levels of the endogenous peptide nociceptin/orphanin FQ became altered in only one of the areas measured, indicating less variance during the estrous cycle. Correlation analyses revealed that significant associations between dynorphin A or dynorphin B and Leu-enkephalin-Arg(6) were found more often during estrus than during the diestrus and proestrus conditions. The ratio between the ir levels of Leu-enkephalin-Arg(6), a cleavage product of the enzymatic conversion of dynorphin peptides into shorter peptides in vivo, and dynorphin peptides was calculated. The significantly lower ratio between Leu-enkephalin-Arg(6) and dynorphin B in diestrus than in proestrus and estrus also indicates cyclic fluctuations in the enzymatic cleavage of dynorphin. These findings are discussed in relation to the possible role of interactions between sex steroids and opioid peptide mechanisms during the normal estrous cycle.

The DREAM of Pain Relief

Chronic pain has manifested itself as an independent disease. Different molecules acting in nociceptive pathways in the periphery and the nervous system are currently under investigation. Recently the multifunctional protein DREAM (D ownstream Regulatory Element Antagonist Modulator)/calsenilin/KChIP3 has been implicated to play a role in the mechanisms of pain modulation and the hypothesis "No DREAM - No pain" was raised. In addition to the binding to DRE (Downstream Regulatory Element) sequences, DREAM/calsenilin/KChIP3 was shown to interact with presenilin, a protein thought to be a key molecule in Alzheimers disease, and Kv4alpha-subunits assembling potassium channels. DREAM/calsenilin/KChIP3 has been described as a Ca2+-dependent transcriptional repressor, which is targeted to the regulatory DNA sequence of the prodynorphin gene. By actively suppressing gene expression of the endogenous opioid receptor ligand dynorphin, DREAM/calsenilin/KChIP3 is modulating the kappa opioid receptor system, which mediates analgesia. DREAM knockout mice showed elevated levels of dynorphin and consequently displayed attenuated chemical induced and inflammatory pain. The data derived from the DREAM knock-out model led to the identification of a novel target in chronic pain management. In this review we focus on DREAM/calsenilin/KChIP3 and its role in pain relief. Keywords: DREAM, calsenilin, KChIP, Kappa opioid receptor, pain, dynorphin

Neuropéptidos en la enfermedad de Alzheimer

Of approximately 200 peptides that are known to exist in the body, 80 carry out functions as neurotransmitters and about 20 have been linked to Alzheimer's disease (AD). In this article we review the most salient studies that have been conducted on neuropeptides such as corticotropin-releasing hormone, thyrotropin-releasing hormone, somatostatin, neuropeptide Y, oxytocin, arginine vasopressin, galanin and insulin, as well as the insulin-like growth factors, the glucagon-like peptides, vasoactive intestinal peptide, cholecystokinin, substance P, opioid peptides and the neuropeptide NAP. Although attempts are made to find a causal association with AD, in many cases the findings are contradictory or not very conclusive. The most notable points could be the reduction in substance P in the cerebral cortex, hippocampus, basal ganglia and cephalospinal fluid; the diminished levels of somatostatin in the same structures except for the basal ganglia; the reduction in the amount of vasopressin except in the temporal lobe; and the increased levels of dynorphin and leucine enkephalin.

Multi-transcriptional profiling of melanin-concentrating hormone and orexin-containing neurons.

1.Melanin-concentrating hormone (MCH) and orexin-containing neurons participate in hypothalamic circuits that control energy homeostasis. While these two systems have projections to widespread target areas within the central nervous system, little is known about intrinsic characteristics and the molecular composition of both the MCH and orexin neurons themselves. 2. By a combinatory approach of quantitative immunocytochemical identification and analysis with laser microdissection and semi-quantitative Real-time RT-PCR, here we present multi-transcriptional profiling of MCH and orexin neurons in the rat lateral hypothalamus. 3. Immunocytochemical analysis showed that orexin peptide expression was increased after fasting both during the activity and resting period of rats, whereas MCH peptide content was only clearly upregulated at resting phase. Subsequent transcriptional profiling showed distinct expression patterns of MCH, orexin and cocaine-amphetamine regulated transcript (CART) between MCH and orexin neurons. A low expression level of dynorphin was found both in MCH and orexin neurons. Receptor expression profiles, reflecting interaction with neuropeptide Y, melanocortins, leptin, glucocorticoids and GABA, showed approximately similar expression patterns among the MCH and orexin neuronal systems. Expression of glutamate- and GABA-markers revealed a possible contributory role of both glutamate and GABA in functional output of MCH and orexin neurons. 4. This method allowed differential screening at mRNA level after immunocytochemical neuron identification and analysis in heterogeneous brain regions, which can further specify functioning of the individual neurons. With respect to MCH and orexin neurons, this study emphasizes that these neurons are targets for stimulatory and inhibitory signals from other brain regions including the arcuate nucleus and the general circulation. Additionally, both glutamate and GABA appear to be involved in MCH and orexin neuronal functioning related to feeding and regulation of the energy balance.

Mice with Chronically Elevated Dopamine Exhibit Enhanced Motivation, but not Learning, for a Food Reward

Dopamine has been critically implicated in learning and motivation, although its precise role remains to be determined. In order to investigate the involvement of dopamine in learning and motivation for a food reward, we used dopamine transporter knockdown mice (DAT KD) that have chronically elevated levels of extracellular dopamine. The present study demonstrates that chronically elevated dopamine enhances tendency to work for a food reward without apparent effects on Pavlovian and operant learning for this reward. The increase in dopamine is associated with elevated levels of dynorphin and Fos B expression in the dorsal caudate-putamen and the core but not the shell subregion of the nucleus accumbens. These data suggest that motivation to work, but not learning, for a food reward appears to be under the critical influence of tonic dopaminergic activity in discrete brain areas relevant for a reward-directed behavior.

Chronic and acute effects of 3,4-methylenedioxy-N-methylamphetamine (‘ecstasy’) administration on the dynorphinergic system in the rat brain

The prodynorphin system is implicated in the neurochemical mechanism of psychostimulants. Exposure to different drugs of abuse can induce neuroadaptations in the brain and affect opioid gene expression. The present study aims to examine the possibility of a common neurobiological substrate in drug addiction processes. We studied the effects of single and repeated 3,4-methylenedioxy-N-methylamphetamine (‘Ecstasy’) on the gene expression of the opioid precursor prodynorphin, and on the levels of peptide dynorphin A in the rat brain. Acute (8mg/kg, intraperitoneally) 3,4-methylenedioxy-N-methylamphetamine markedly raised, two hours later, prodynorphin mRNA levels in the prefrontal cortex, and in the caudate putamen, whereas it decreased gene expression in the ventral tegmental area. Chronic (8mg/kg, intraperitoneally, twice a day for 7 days) 3,4-methylenedioxy-N-methylamphetamine increased prodynorphin mRNA in the nucleus accumbens, hypothalamus and caudate putamen and decreased it in the ventral tegmental area. Dynorphin A levels increased after chronic treatment in the ventral tegmental area and decreased after acute treatment in the nucleus accumbens, prefrontal cortex and hypothalamus. These findings confirm the role of the dynorphinergic system in mediating the effects of drugs of abuse, such as 3,4-methylenedioxy-N-methylamphetamine, in various regions of the rat brain, which may be important sites for the opioidergic mechanisms activated by addictive drugs.

Morphine-induced changes in the activity of proopiomelanocortin and prodynorphin systems in zymosan-induced peritonitis in mice

We have shown that supplementation of proinflammatory agent with a high dose of morphine not only abolishes inflammation-related pain symptoms but also inhibits influx of leukocytes to the inflamed peritoneal cavity. Present investigations focused on effects of morphine on proopiomelanocortin and prodynorphin systems during zymosan-induced peritonitis. Males of SWISS mice were ip injected with zymosan (Z, 40 mg/kg) or zymosan with morphine (ZM, 20 mg/kg). At time 0 (controls) and 4 and 24 h after stimulation, peritoneal leukocytes (PTLs) were counted, PTL levels of opioid peptides (β-endorphin and dynorphin) measured by radioimmunoassays, while mRNAs coding their respective precursors (POMC and PDYN) and receptors (MOR and KOR) determined by QRT-PCR. Influx of inflammatory PTLs, mainly PMNs, was significantly delayed by morphine co-injection. Total levels of β-endorphin and dynorphin corresponded with PTL numbers, while levels per cell were similar in all groups except of β-endorphin, decreased in ZM at 4 h. Levels of both peptides in peritoneal fluid were increased in Z and ZM groups at 4 h, while at 24 h only in case of β-endorphin in Z group. POMC was increased only in ZM group at 4 h of peritonitis, while PDYN in both Z and ZM groups at the same time. MOR mRNA was increased 24 h after injection in Z and ZM groups, while KOR mRNA was similar in all groups except of decrease in Z at 24 h. In conclusion, endogenous opioids and their receptors are involved in zymosan-induced peritonitis and affected in various ways by morphine co-injection.

The antidepressant effect of running is associated with increased hippocampal cell proliferation

A common trait of antidepressant drugs, electroconvulsive treatment and physical exercise is that they relieve depression and up-regulate neurotrophic factors as well as cell proliferation and neurogenesis in the hippocampus. In order to identify possible biological underpinnings of depression and the antidepressant effect of running, we analysed cell proliferation, the level of the neurotrophic factor BDNF in hippocampus and dynorphin in striatum/accumbens in 'depressed' Flinders Sensitive Line rats (FSL) and Flinders Resistant Line (FRL) rats with and without access to running-wheels. The FRL strain exhibited a higher daily running activity than the FSL strain. Wheel-running had an antidepressant effect in the 'depressed' FSL rats, as indicated by the forced swim test. In the hippocampus, cell proliferation was lower in the 'depressed' rats compared to the control FRL rats but there was no difference in BDNF or dynorphin levels in striatum/accumbens. After 5 wk of running, cell proliferation increased in FSL but not in FRL rats. BDNF and dynorphin mRNA levels were increased in FRL but not to the same extent in the in FSL rats; thus, increased BDNF and dynorphin levels were correlated to the running activity but not to the antidepressant effect of running. The only parameter that was associated to basal level of 'depression' and to the antidepressant effect was cell proliferation in the hippocampus. Thus, suppression of cell proliferation in the hippocampus could constitute one of the mechanisms that underlie depression, and physical activity might be an efficient antidepressant.

Pathobiology of dynorphins in trauma and disease.

Dynorphins, endogenous opioid neuropeptides derived from the prodynorphin gene, are involved in a variety of normative physiologic functions including antinociception and neuroendocrine signaling, and may be protective to neurons and oligodendroglia via their opioid receptor-mediated effects. However, under experimental or pathophysiological conditions in which dynorphin levels are substantially elevated, these peptides are excitotoxic largely through actions at glutamate receptors. Because the excitotoxic actions of dynorphins require supraphysiological concentrations or prolonged tissue exposure, there has likely been little evolutionary pressure to ameliorate the maladaptive, non-opioid receptor mediated consequences of dynorphins. Thus, dynorphins can have protective and/or proapoptotic actions in neurons and glia, and the net effect may depend upon the distribution of receptors in a particular region and the amount of dynorphin released. Increased prodynorphin gene expression is observed in several disease states and disruptions in dynorphin processing can accompany pathophysiological situations. Aberrant processing may contribute to the net negative effects of dysregulated dynorphin production by tilting the balance towards dynorphin derivatives that are toxic to neurons and/or oligodendroglia. Evidence outlined in this review suggests that a variety of CNS pathologies alter dynorphin biogenesis. Such alterations are likely maladaptive and contribute to secondary injury and the pathogenesis of disease.

Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure

The opioid analgesics, commonly exemplified by morphine, represent the best option for the treatment of severe pain and for the management of chronic pain states, of both malignant and nonmalignant origin. It is well recognized that the prolonged use of opioids is associated with a requirement for ever-increasing doses in order to maintain pain relief at an acceptable and consistent level. This phenomenon is termed analgesic tolerance. While the concept that tolerance can develop as a result of cellular adaptations to the presence of the opioid has been proposed, it is now becoming abundantly clear that tolerance may also be related to a state of hyperalgesia that results from exposure to the opioid itself. Patients who receive long-term opioid therapy sometimes develop unexpected, abnormal pain. Similar paradoxical opioid-induced pain has been confirmed in a number of animal studies, even during the period of continuous opioid delivery. A number of recent studies have demonstrated that such pain may be secondary to neuroplastic changes that occur in the brain and spinal cord. One such change may be the activation of descending pain facilitation mechanisms arising from the rostral ventromedial medulla (RVM) elicited in part by increased activity of cholecystokinin (CCK) in the RVM. A cascade of pronociceptive events may follow, such as opioid-induced upregulation of spinal dynorphin levels that promotes enhanced input from primary afferent nociceptors. This mechanism appears to depend on intact descending pathways from the RVM, since interrupting this pathway abolishes enhanced abnormal pain. Furthermore, extended opioid exposure also can elicit increased calcitonin gene related peptide (CGRP) and substance P expression in the dorsal root ganglia. It is probable that increased pain elicited by opioids is a critical factor in the behavioral manifestation of opioid tolerance because the same manipulations that block abnormal pain also block antinociceptive tolerance. Taken together, such studies show that opioids elicit systems-level adaptations resulting in pain due to descending facilitation, upregulation of spinal dynorphin, and enhanced, evoked release of excitatory transmitters from primary afferents. These adaptive changes in response to sustained exposure to opioids indicate the need for the evaluation of the clinical consequences of long-term opioid administration. Additionally, these findings suggest a need for novel chemistry involving design of agents that may counteract opiate-induced neuroplastic adaptations resulting in pain relief without analgesic tolerance.

Relative contribution of endogenous opioids to myocardial ischemic tolerance 1

Background Opioid preconditioning by exogenous opioids experimentally protects the myocardium against ischemia/reflow injury. Additionally, endogenous opioid peptides released during ischemia also enhance ischemic tolerance. Promiscuous opioid receptor agonists conceal the differential contribution of the mu (μ), delta (δ), and kappa (κ) opioid subtypes. This study compared the impact of selective δ and κ opioid receptor antagonists on postischemic functional and metabolic recovery. Also measured were changing levels of peptides dynorphin B and met-enkephalin during ischemia/reflow injury. Materials and methods Using the rabbit Langendorff model, the functional recovery of control hearts (following 2 h of global ischemia) was compared to hearts pretreated with δ antagonist NTB (1 μ m) or κ antagonist, nor-BNI (1 μ m). Measures included percentage of return of isovolumetric developed pressure (LVDP), myocardial oxygen consumption (MVO 2) and coronary flow (CF). In additional studies, untreated hearts were harvested at baseline, following ischemia, or following 5 or 45 min of reflow. Tissue concentrations of met-enkephalin and dynorphin B were measured by RIA. Results After 45 min of reflow, hearts pretreated with either NTB or nor-BNI showed impaired functional recovery by a decrease in LVDP ( P < 0.05); however, MVO 2 or CF were unaffected. RIA data shows that baseline levels of both peptides are similar and increase significantly during ischemia, but reflow dynorphin levels drop far below baseline, while met-enkephalin returns to baseline. Conclusion Antagonism of both δ and κ opioid receptor subtypes equally contributes to impaired left ventricular function, independent of altered perfusion or metabolic rate. Endogenous κ-receptor agonists may contribute primarily during ischemia or early reflow, since low late reflow dynorphin content did not correlate with altered functional recovery.