Opiate Pharmacology Research Articles

Opiates and the adrenal: the tip of the iceberg?

Morphine-like compounds based on opium and derived from the opium poppy, Papaver somniferum, have been known for millennia, and their use recurs throughout the ages in personal reports and in world literature. For many decades their use was, if not fully condoned by society, tolerated as an effective means of ameliorating pain and indeed for ‘recreational’ purposes. The Opium Wars in the nineteenth century pitched the enthusiastic British traders in China against the local authorities who wished to control their use, with the eventual triumph of commercial capitalism and British firepower. In late nineteenth century London such opium dens were an accepted part of the Limehouse landscape, at least according to Charles Dickens, and frequented by well-connected gentlemen; indeed Coleridge’s epic poem Kubla Khan was said to be written under the influence of opium, while Thomas de Quncey immortalised the habit in his Confessions of an English Opium-Eater. However, over time and especially in the twentieth century, such opium-like compounds, the opiates, increasingly became drugs of abuse in addition to their profound analgesic effects, with heroin in particular becoming a global scourge. In addition, various analogues of the opiates were synthesised, with varying potencies, hoping to emphasise the analgesic efficacy while limiting their addictive potential. Unfortunately, it has been difficult to separate these two factors, and with the active encouragement of pharmaceutical companies, drugs such as oxycodone have become a major source of addiction and distress. Thus, in addition to their widespread use as highly effective analgesic agents in medicine, opiates have moved from an illegal phenomenon as part of the global drug trade to a phenomenal prescription-agent problem in many parts of the developed world. It has been estimated that since 1999, 200 000 Americans have died from oxycodone and allied prescription opiates, while in recent years US clinicians have issued a quarter of a billion opiate prescriptions annually (1). The pharmacology of opiates has become literally of deadly interest. Thus, their pharmacology, and especially their effects on neuroendocrine axes, is of very considerable interest.

Pain in patients with cancer.

Pain is an important concern in patients with cancer who are receiving active treatment and in long-term cancer survivors. It is one of the most feared aspects of cancer, and it can have a major adverse impact on quality of life. It has long been recognized that untreated or undertreated pain is common in patients with cancer, with little evidence of recent improvement. 1,2 Given the many advances in knowledge regarding cancer pain and its management over the past decade, this Special Series issue was assembled to provide readers with an update on the current understanding of the biology of cancer pain, the biology and mechanisms of action of the opioids used to treat cancer pain, challenges in the management of cancer pain, and evidence-based multidisciplinary approaches to management of cancer pain. We hope that the articles in this Special Series issue will enhance clinician understanding of cancer pain and its treatment and provide practical approaches to managing pain in patients with cancer. Hui and Bruera 3 outline “A Personalized Approach to Assessing and Managing Pain in Patients With Cancer.” They provide a practical yet evidence-based approach to personalized pain assessment and management in the clinic. They also discuss a paradigm shift in pain management, outlining a multistep approach that includes systematic screening, comprehensive pain assessment, characterization of pain, identification of personal modulators of pain expression, documentation of personalized pain goals, and implementation of a multidisciplinary treatment plan with subsequent customized longitudinal monitoring. Their article summarizes an expert clinician’s approach to pain management and provides practical tables and figures that will be helpful to the clinician who manages cancer pain. Falk and Dickenson 4 discuss the biology of pain in patients with cancer, with a special focus on bone pain, in their article entitled “Pain and Nociception: Mechanisms of Cancer-Induced Bone Pain.” The authors review mechanisms of cancer pain, stating that it is a “complex pain state involving components of both inflammatory and neuropathic pain, but also displaying elements that appear to be unique to cancer pain.” They discuss cancer pain as unpredictable, with highly variable intensity, which makes it difficult to manage. They also review mechanisms of acute pain, neuropathic pain, inflammatory pain, and complex cancer pain, providing informative figures that will help clinicians understand the biology of pain and may help guide the selection of management approaches. Gavril Pasternak 5 reviews “Opiate Pharmacology and Relief of Pain,” a complex area that is presented in a clear fashion. Pasternak states that opioids “selectively impact the hurt of nociceptive stimuli”; they act through activation of a pain modulating system consisting of endogenous opioid peptides and their receptors. He discusses three classes of opioid/receptors—mu, delta, and kappa—and suggests that individual responses to specific opioids may reflect differences in the biology of these receptors. Pasternak discusses important issues such as opioid cross tolerance, benefits, and risks of opioid rotation and the growing understanding of mu receptor subtypes, introducing the

Opiate pharmacology and relief of pain.

Opioids remain the mainstay of severe pain management in patients with cancer. The hallmark of pain management is individualization of therapy. Although almost all clinically used drugs act through mu opioid receptors, they display subtle but important differences pharmacologically. Furthermore, not all patients respond equally well to all drugs. Evidence suggests that these variable responses among patients have a biologic basis and are likely to involve both biased agonism and the many mu opioid receptor subtypes that have been cloned.

Hans Walter Kosterlitz. 27 April 1903 — 26 October 1996

Hans Walter Kosterlitz will be remembered as the winner of an international race to identify the first endogenous opioid, enkephalin. He came to the UK from Berlin in 1934, one of the many scientific émigrés of that period who later so enriched biochemistry, physiology and pharmacology. His entire career was spent at the University of Aberdeen, where he developed a reputation first in carbohydrate metabolism and later in the pharmacology of opiates. His strong experimental skills, and particularly the use of bioassays on tissues from laboratory animals, allowed him to predict the effectiveness and abuse potential of opiate drugs. Most notably, this led to the isolation of the peptide hormone enkephalin, the first of a group of such peptides now often known as endorphins. This work was done in his seventies, after his official retirement, with an energy and enthusiasm that could leave younger colleagues physically tired but intellectually stimulated.

Manifold implications of forgotten hyperglycemia in clinical opiate dependence

Both chronic opiate dependence and diabetes are widespread public health problems. The historically causal relationship between opiate pharmacology and hyperglycemia would appear to have fallen from curent medical knowledge. The aims of this study were to assess the severity of hyperglycemia in our opiate substance use disorder (SUD) patient population and review its pathophysiological basis. A review was undertaken of our clinical pathology database, comparing SUD patients and general medical controls (NSUD). A total of 1,602 SUD patients were compared with 2,858 NSUD patients 15–50 years of age. Mean ages were 31.29 ± 7.40 and 31.55 ± 9.17 years, respectively (P = 0.42) and were 68.60 and 52.76% male (P < 0.0001). The glycosylated hemoglobin (HbA1c) level in diabetics was 8.14 ± 2.76 and 6.29 ± 1.88 (P = 0.0032). In a nested case-control subset, random glucose, HbA1c, and fructosamine levels were all significantly elevated (P < 0.05). Adjusted for age, the HbA1c level was elevated among the SUD group (P < 0.0001) the age at addiction interaction was also significant (P < 0.0001). Serum glucose, HbA1c, fructosamine, and microalbumin levels were shown to be biomarkers of age. At multiple regression analysis, interactions between age, addictive status, glycemia, and the inflammatory markers, ethrocyte sedimentation rate and C-reactive protein, were significant (P < 0.05). At age 50, diabetic SUD patients had a HbA1c of 8.31%, which was equivalent to that of NSUD patients at age 140.54 years, a 181.07% elevation. These results confirm that hyperglycemia is higher in both an absolute and an age-dependent sense among diabetic SUD patients. These results are consistent with an acceleration of age-related and degenerative pathologies in many tissues and therefore carry far-reaching implications for the safety of indefinite opiate maintenance.

Pharmacological characterization of a nociceptin receptor from zebrafish (Danio rerio)

The nociceptin receptor (NOP) and its endogenous ligand, nociceptin/orphanin FQ (OFQ), are involved in a wide range of biological functions, such as pain, anxiety, learning, and memory. The zebrafish has been proposed as a candidate to study the in vivo effects of several drugs of abuse and to discover new pharmacological targets. We report the cloning, expression, and pharmacological characterization of a NOP receptor from zebrafish (drNOP). The full-length cDNA codes a protein of 363 residues, which shows high sequence similarity to other NOPs. Phylogenetic analysis indicates that NOPs are broadly conserved during vertebrate evolution, and that they stand for the most divergent clade of the opioid/OFQ receptor family. Expression studies have revealed that drNOP mRNA is highly expressed in the central nervous system, and low expression levels are also found in peripheral tissues such as gills, muscle, and liver. Pharmacological analysis indicates that drNOP displays specific and saturable binding for [Leucyl-3,4,5-(3)H]nociceptin, with a K(d)=0.20 ± 0.02 nM and a B(max)=1703 ± 81 fmol/mg protein. [(3)H]Nociceptin binding is displaced by several opioid ligands such as dynorphin A (DYN A), naloxone, bremazocine, or the κ-selective antagonist nor-binaltorphimine. [(35)S]GTPγS stimulation studies showed that drNOP receptor is functional, as nociceptin is able to fully activate the receptor and DYN A behaves as a partial agonist (50% stimulation). Our results indicate that drNOP receptor displays mixed characteristics of both NOP and κ opioid receptors. Hence, drNOP, which has retained more of the likely ancestral features, bridges the gap between nociceptin and opiate pharmacology.

Opiates, Sleep, and Pain

Opiates, Sleep, and Pain

Gender-related differences in the pharmacokinetics of opiates

Previous studies have documented gender-related differences in a number of aspects of the pharmacology of opiates, including their analgesic activity, stimulative properties and generation of physical dependence. The current experiments were carried out with the aim to examine whether male–female differences exist in the blood and brain levels of opiates attained after their intraperitoneal injection to male and female Wistar rats. The tests were performed 5, 15, 45 and 120 min after the animal treatment with seized heroin. Gas chromatography–mass spectrometry (GC–MS) method was developed to quantitatively determine opiate alkaloids in blood and brain regions (known for their high concentration of μ-opiate receptors): cortex, brainstem, amygdala and basal ganglia. Maximal contents of opiates in blood of animals of both genders were found in the second measurement time (15 min), the values measured in the males being significantly higher, which suggests a faster passage of the opiates from blood to brain tissue in female animals. The highest content of opiates in the brain tissue of female animals was measured 15 min and with male animals 45 min after the treatment, which also indicates faster distribution of opiates from blood to brain in the female compared to male rats. The highest proportion of opiates was found in the basal ganglia of the animals of both genders. The obtained results offer the possibility of selecting this part of the brain tissue of both males and females as a representative sample for identifying and assessing contents of opiates.

Opiate Pharmacology of Intrathecal Granulomas

Opiate Pharmacology of Intrathecal Granulomas

Opiate Pharmacology of Intrathecal Granulomas

Chronic intrathecal morphine infusion produces intradural granulomas. The authors examined a variety of opioids infused intrathecal for analgesic activity and toxicity. Two sets of experiments were undertaken in dogs with chronic intrathecal catheters: (1) Six-hour intrathecal infusions were used to determine the full analgesic dose and the maximum tolerated dose. (2) To establish toxicity, the maximum tolerated dose was given for up to 28 days by continuous intrathecal infusion. Drugs examined were morphine sulfate, hydromorphone, D/L-methadone, L-methadone, D-methadone, fentanyl, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO), naloxone, or saline. RESULTS ANALGESIA AND TOLERABILITY: Six-hour intrathecal infusion of agonists resulted in a time-dependent increase in thermal escape latency. At higher concentrations, dose-limiting motor dysfunction and sedation occurred, and hypersensitivity occurred. The concentrations, in mg/ml, for full analgesic dose/maximum tolerated dose were as follows: morphine, 0.9/12.0; hydromorphone, 1.0/3.0; D/L-methadone, 2.8/3; L-methadone, 1.0/> 1.0; fentanyl, 0.3/2.0; DAMGO, 0.1/> 2.0; D-methadone, > 1/> 1; naloxone, > 10/> 10. SPINAL PATHOLOGY: Chronic intrathecal infusion of the maximum tolerated dose revealed 100% intradural granuloma formation after morphine, hydromorphone, L-methadone, and naloxone. DAMGO induced a mass in only a single animal (one of three). D/L- and D-methadone produced intradural granulomas but were also associated with parenchymal necrosis. Saline and fentanyl animals displayed no granulomas. Intrathecal opiate-induced granulomas are not strictly dependent on opioid receptor activation. Therefore, opiates at equianalgesic doses present different risks for granuloma formation. Importantly, D/L- and D-methadone also resulted in parenchymal necrosis, an affect associated with the N-methyl-D-aspartate antagonist action of the D-isomer.

Conversation with Charles R. Schuster.

Conversation with Charles R. Schuster.

Gender differences in the intravenous self-administration of mu opiate agonists

Gender differences have been observed in a number of aspects of the pharmacology of opiates, including their antinociceptive activity, discriminative stimulus properties, the generation of physical dependence, and their positive reinforcing properties. The current experiments were carried out to rigorously examine whether gender differences exist in the intravenous (IV) self-administration of opiates in an operant conditioning paradigm. Both dose–response analyses and the determination of the strength of the reinforcing properties of opiates using a “breakpoint” analysis were examined. We found strong gender differences in the IV self-administration of two mu opiate agonists—heroin and morphine. At a standard fixed ratio (FR) of responding, females consumed significantly greater amounts of heroin and morphine than did males in a dose-dependent fashion. In addition, females also showed much higher breakpoints than did males: the highest FR breakpoint achieved in females was more than double that observed in males and the frequency distribution of breakpoints was shifted significantly to the right in females when compared to males. These data collectively show that mu opiate agonists may serve as reinforcing agents in females over a broader dose range than males and that they also self-administer considerably more opiates on a milligram per kilogram basis. Finally, we conclude that they will also expend much greater effort in an operant conditioning task to obtain opiate reinforcement.

From Opiate Pharmacology to Opioid Peptide Physiology

This is a personal account of how studies of the pharmacology of opiates led to the discovery of a family of endogenous opioid peptides, also called endorphins. The unique pharmacological activity profile of opiates has an endogenous counterpart in the enkephalins and β-endorphin, peptides which also are powerful analgesics and euphorigenic agents. The enkephalins not only act on the classic morphine (μ-) receptor but also on the δ-receptor, which often co-exists with μ-receptors and mediates pain relief. Other members of the opioid peptide family are the dynorphins, acting on the κ-receptor earlier defined as precipitating unpleasant central nervous system (CNS) side effects in screening for opiate activity. A related peptide, nociceptin is not an opioid and acts on the separate NOR-receptor. Both dynorphins and nociceptin have modulatory effects on several CNS functions, including memory acquisition, stress and movement. In conclusion, a natural product, morphine and a large number of synthetic organic molecules, useful as drugs, have been found to probe a previously unknown physiologic system. This is a unique development not only in the neuropeptide field, but in physiology in general.

Regulation of calbindin-D 28K gene expression in response to acute and chronic morphine administration

The effect of acute and chronic morphine administration on calbindin-D 28K (calbindin) gene expression has been studied. One group of adult male rats received a single injection of morphine (10 mg/kg, s.c.) or saline and were sacrificed 1 or 4 h later. Another group was injected with escalating doses of morphine sulfate twice daily for 15 days to induce tolerance and physical dependence. Rats were sacrificed 1 h after the last injection. In a third group, the effect of naloxone-precipitated withdrawal on gene expression in morphine-addicted rats was also analyzed 1 h after naloxone (1 mg/kg. i.p.). The cerebellum and remaining brain (minus the cerebellum) were removed, and total RNA was extracted and used for analysis. Calbindin mRNA levels in cerebellum were decreased to 30%–40% control at 1 and 4 h after a single morphine injection. Co-administration of the opiate antagonist, naloxone, reversed the effect of morphine. Tolerance developed to the acute effects in that levels were not altered significantly 1 h after morphine injection in chronically-treated rats. Unlike the cerebellum, calbindin mRNA in the remainder of the brain (minus the cerebellum) was unchanged 1 and 4 h following morphine administration to drug-naive rats, but was increased more than 2-fold compared to controls 1 h after morphine injection in chronically treated animals. Naloxone-precipitated withdrawal caused a small (20%) but significant decrease in calbindin mRNA in the cerebellum, with no change in the brain (minus the cerebellum). Rapid changes in calbindin gene expression in the cerebellum following morphine injection may play a role in acute opiate pharmacology, and the increase in calbindin expression in the brain (minus the cerebellum) may be an important aspect of the adaptation of the nervous system that results in decreased sensitivity to morphine following chronic administration.

Mechanisms of morphine-induced immunomodulation

The concept of opiates as immunomodulatory agents dates to the turn of this century [l, 21. By the 194Os, many studies had been carried out on the effects of opiates on immune cells and on resistance of animals to infection [reviewed in Ref. 31. Also, most of the infectious disease complications of intravenous opiate abuse were well recognized [4]. Several decades elapsed, however, before interest in this topic was rekindled by the observation that cellmediated immune function is impaired in heroin addicts [5] and by reports in 1979 and 1980 that the major cell types involved in cell-mediated immunityT-lymphocytes and mononuclear phagocytes-possess opiate receptors [6-8]. Thus, the stage was set in 1981, the outset of the acquired immunodeficiency syndrome (AID%) epidemic, for intensive research in this area of immunology, once it became established that injection drug use was a prominent risk factor for this devastating infectious disease [9]. In addition to the potential relevance of opiateinduced immunomodulation to AIDS, progress in this area has been spurred by developments in two related fields. First, major advances have been made in the field of opiate pharmacology, especially in the delineation of selective classes of opioid receptors [reviewed in Ref. lo]. Second, new concepts have been derived from the field of “psychoneuroimmunology” regarding bidirectional communication between the neuroendocrine and immune systems [reviewed in Refs. 11 and 121. Studies in this multidisciplinary area of research have demonstrated a dynamic interaction between these two systems through chemical mediators, including endogenous opioid peptides. Not only have all three classes of endogenous opioid peptides been shown to affect immune cell function, but immunocytes

Intraspinal opiates for treatment of intractable pain in the terminally ill cancer patient.

The discovery of opiate receptors and then their endogenous ligands in 1974 (Snyder et al., 1974) has elucidated a vast pharmacology of opiates providing a basis for their diverse clinical applications. With the awareness of quality of life as a primary goal in terminal cancer patients, widespread attention has been drawn to the direct delivery of long-term intraspinal analgesics to cancer patients for who all medical pain control regimens have failed (Coombs & Saunders, 1974). Intraspinal administration of opiates and nonopiate analgesics is not only appealing on theoretical grounds but provides a minimally invasive method to insure otherwise unobtainable pain relief while eliminating obtundation and systemic side-effects associated with conventional therapy (Cobb et al., 1984; Harbaugh et al., 1982; Leavens et al., 1982; Malone et al., 1985; Onofrie et al., 1981; Poletti et al., 1981). Although intraspinal opiates have been used in the treatment of postoperative and benign-pain syndromes (Asari et al., 1981; Cousins & Mather, 1984), in our discussion we review the basic science, current techniques and possible future improvements in spinal analgesia in the control of chronic cancer pain.

Opioid peptide levels in gerbil brain after transient ischemia: lasting depletion of hippocampal dynorphin.

Peptides derived from each of the 3 endogenous opioid precursors were measured in gerbil brain regions at various times after transient bilateral carotid artery occlusion using radioimmunoassays specific for beta-endorphin-, met-enkephalin-, and dynorphin A-related peptides. Lasting changes were observed only in the hippocampus. The most striking effect was on dynorphin A immunoreactivity, which was reduced by 30-40% as early as 1 hour after recirculation and remained at 50% of the control level for at least 1 week. In some experiments dynorphin levels showed a transient recovery at 24 hours. These results demonstrate a unique sensitivity of the dynorphin-containing dentate granule cell-mossy fiber pathway to transient ischemia. Although these cells remain histologically intact, the decrease in dynorphin level precedes and continues during the delayed loss of hippocampal CA1 neurons characteristic of this model and further defines the selective vulnerability of hippocampal circuitry following ischemia. These observations clearly identify the hippocampus as a well-defined brain region in which further studies of the postischemic pathophysiology of endogenous opioid peptides may provide a rational basis for evaluating the place of opiate pharmacology in stroke treatment.

Pharmacology of Opiates and Their Derivatives

Abstract: The opiates or opioids are exogenous substances which bind in a stereospecific and saturable manner to several subspecies of cell membrane receptors which are sites of action of endogenous ligands (enkephalins, B‐endorphine). The opiates, which have common structural features, are agonists or partial agonists, the potency of which generally correlates well with affinity for opiate receptors. Many of the actions of opiates are related to alteration of the release of endogenous neurotransmitters. Inhibition of intracelluar adenylate cyclase and altered transmembrane calcium fluxes also appear to be important consequences of opiate action. Most opiates share the pharmacological properties of morphine. The development of tolerance and physical dependence with chronic administration is a characteristic feature of all opiates limiting their clinical use and creating the liability for abuse. With established opiate tolerance, cessation of the drug is accompanied by a characteristic withdrawal syndrome which is suppressed by opiate administration and can also be precipitated by an opiate antagonist such as naloxone. Many of the differences between opiates are due to different pharmacokinetic properties, particularly oral bioavailability and elimination rate. The search for a non‐addictive opiate analgesic continues but is presently foiled by the inherent pharmacological properties of these drugs.

Sites and mechanisms of basic narcotic receptor function based on current research

Within the past decade, progress in opiate pharmacology has been phenomenal and has stimulated widespread interest. Several potent endogenous peptides with morphine-like activity were isolated and their structures were established. Opioid receptors in the brain were localized and characterized. Plausible hypotheses to explain the mechanism of action of the narcotic analgetics have been proposed. Antagonist-agonists that are potent analgesics with low addition liability were introduced for clinical application. Epidural administration of morphine and its surrogates to reduce side effects and prolong drug action is gaining increasing popularity. Extensive research is ongoing concerning the use of opioids in the treatment of shock and the mental states. Some of these advances will be discussed.

Yohimbine exacerbates and clonidine attenuates acute morphine withdrawal in rats

The involvement of α2-noradrenergic receptors in the expression of opiate withdrawal was studied using an operant behavioral model of acute morphine dependence. Clonidine, an α2-agonist, attenuated and yohimbine, an α2-antagonist, exacerbated the naloxone-induced suppression of fixed ratio 15 responding in rats pretreated several hours earlier with a single, moderate dose of morphine. These data indicate that the α2-agonist action of clonidine is responsible for its amelioration of withdrawal symptoms. It also validates the acute dependence model for studying the pharmacology of opiates and associated adaptive processes.