Multiple opioid receptor systems in brain and spinal cord: Part I

The biological activity of opioid agents reflects their interaction with specific membrane sites. The fact that the drug interaction resulting in physiological responses shows distinguishing characteristics with regard to rank order of agonist potency, affinity of the antagonist for the site acted upon by the agent to produce the effect, tolerance and cross-tolerance, may be interpreted as indicating that different opioids produce their effects by an action on distinctive receptors. Examination of the literature provides support for the hypothesis proposed by different investigators that the physiological effects of the several opioid ligands may be parsimoniously explained in terms of several possibly overlapping receptor classes including mu, delta, kappa, sigma and epsilon. Binding studies examining the affinity of the ligand for a tissue site have in general provided confirming support for these receptor profiles. It is stressed that the majority of the documentation for receptor classes derives from in vitro work. However, a growing number of quantitative studies of the receptors in brain which regulate central nervous system processing are also showing evidence of definable differences in drug action which are comparable to those reported for in vitro bioassays and binding studies. Examination of the pharmacology of the analgesic effects of opioids indicates that the differences in the activity of opioid drugs (such as between mu and kappa agonists) probably reflect the role of different pain processing systems. Though not reviewed, it is likely that a similar complexity underlies the interaction of opioids with neural substrates mediating other functions. Thus different opioid receptors may modulate the same physiological phenomenon because they are on different systems which have a similar output (e.g. spinal reflex inhibition) or they may co-exist on the same neurone. In short, it appears likely that there are discriminable populations of opioid receptors and that no single receptor can be said to modulate a given physiological effect.     

Opioids modulate human neutrophil and lymphocyte function: thermal injury alters plasma beta-endorphin levels

To investigate the role of opioids in the acquired immune dysfunctional state that occurs after burns or trauma, plasma beta-endorphin levels were measured serially in nine severely burned patients, and the effect of four different opioids on normal neutrophil and lymphocyte function was quantitated. The rationale for these studies is that the neuroendocrine system appears capable of interacting with and modulating immune function. The plasma levels of beta-endorphin increased to higher than normal during the first 36 hours after burn (15 versus 3.4 pmol/L, p less than 0.05) but quickly returned toward normal. Morphine had the most profound effect on in vitro neutrophil function; it decreased neutrophil chemotaxis but increased neutrophil bactericidal activity for Staphylococcus aureus, as well as resting and zymosan-stimulated oxygen consumption. Other opioids (naloxone, met-enkephalin, and beta-endorphin) had no direct effect on neutrophil chemotaxis or bactericidal activity. Both naloxone and met-enkephalin increased neutrophil oxygen consumption in a dose-dependent fashion, whereas beta-endorphin impaired neutrophil oxygen consumption. None of the opioids altered resting lymphocyte blastogenesis. The only opioid that impaired the ability of normal lymphocytes to respond to mitogen stimulation at physiologically relevant doses was beta-endorphin. These results, documenting that beta-endorphin levels are altered after thermal injury and that opioids can modulate normal neutrophil and lymphocyte function in vitro, support the concept that changes in neuroendocrine activity may occur and potentially alter immune function.     

Peripheral beta-endorphin and pain modulation.

Beta-endorphin is a peptide with morphine-like effects produced primarily in the anterior lobe of the pituitary gland. After its cleavage from the parent molecule, proopiomelanocortin, beta-endorphin is circulated via the blood stream to interact with specific opioid receptors located throughout the body. The peptide produces analgesia by inhibiting the firing of peripheral somatosensory fibers. It also affects other senses, such as vision, hearing, and smell. Whereas the ability to increase beta-endorphin secretion during times of surgical stress is positively correlated with amelioration of pain, the administration of exogenous opioids, such as fentanyl, reduces plasma beta-endorphin. Decreased beta-endorphin concentrations may play a role in trigeminal neuralgia, migraine headache, and rheumatoid arthritis.     

Receptors, G proteins, and their interactions

Membrane receptors coupling to intracellular G proteins (G protein-coupled receptors) form one of the major classes of membrane signaling proteins. They are of great importance to the practice of anesthesiology because they are involved in many systems of relevance to the specialty (cardiovascular and respiratory control, pain transmission, and others) and many drugs target these systems. In recent years, understanding of these signaling systems has grown. The structure of receptors and G proteins has been elucidated in more detail, their regulation is better understood, and the complexity of interactions between the various parts of the system (receptors, G proteins, effectors, and regulatory molecules) has become clear. These findings may help explain both actions and side effects of drugs. In addition, these newly discovered targets are likely to play important roles in disease states of relevance to anesthesiologists.     

Respiratory depression following administration of low dose buprenorphine as postoperative analgesic after fentanyl balanced anaesthesia

Opioids are among the most ancient and widely used drugs in anaesthesiology. The pharmacology of opioid analgesics and their receptors is a complex and not fully understood matter; even more complex are the interactions between different classes of opioids at both molecular and clinical levels. We want to report here a clinical observation to emphasize the importance of the theoretical basis of anaesthesiology. This paper contains a clinical observation of respiratory depression following the administration of buprenorphine as postoperative analgesic after balanced anaesthesia with fentanyl. The observed case is interpreted in the light of the pharmacokinetics and pharmacodynamics of the different classes of opioid drugs (agonists, agonists–antagonists, antagonists) and of the interactions with their respective receptors.     

Pharmacological approaches other than opioids in chronic non-cancer pain management

Many pains are controlled by non-addictive procedures ranging from exercise to a variety of analgesic medications. Some pains are controlled by analgesic drugs, but at the cost of intolerable side effects. This is true both for non-steroidal anti-inflammatory drugs and opioids. The worst pains are most often controlled by opioids, but problems of tolerance and addiction limit these successes. This contribution provides a statement on non-addictive, non-opioid drugs which help to control pain. Just as these vary in their success, so they vary also in the strength of the scientific evidence which supports their use. The groups of drugs to be considered can be evaluated in three respects; evidence of analgesic effect in controlled trials; evidence of side-effects compared with control substances and with standard experience; evidence of usefulness in clinical practice. The latter which is the most important for practice often has the least scientific proof. Six main classes of drugs are recognized which provide analgesic effects, other than opioids. 1) Non-steroidal anti-inflammatory drugs are widely accepted as analgesics on the basis of animal studies, numerous controlled investigations and clinical practice. Acetaminophene may not be anti-inflammatory, but is recognized as an effective analgesic which in many other respects resembles the above. 2) Muscle relaxants, e.g. cyclobenza-prine or baclofen have varied actions, but often provide some relief of pain. 3) Antidepressants may be analgesic if they relieve depression which is giving rise to pain. This applies to all antidepressants. Some antidepressants have been shown to be analgesic in the absence of depression. The best accredited of these is amitriptyline. Antidepressants too have significant side effects. A serotoninergic hypothesis is insufficient to explain the actions of antidepressants in relieving pain in the absence of depression. 4) Phenothiazine neuroleptics (and possibly some others) may be analgesic. Drugs reported to be analgesic include chlorpromazine, fluphenazine, perphenazine, trifluoperazine, methotrimeprazine (levomepromazine) among others. Halope-ridol has also been utilized. Well controlled evidence exists with the use of methotrimeprazine (levomepromazine) used as an injection. The analgesic effect of oral neuroleptics is less well established and mostly depends upon clinical observation, withdrawal and re-challenge. 5) Anticonvulsants. 6) Other drugs. Non-steroidal anti-inflammatory drugs and some muscle relaxants, e.g. cyclobenzaprine are best used in the short term. The gastrointestinal side effects of non-steroidal anti-inflammatory drugs have been quite troublesome and over 2% of patients followed over five years are at risk of developing peptic ulceration from such medication. Cyclobenzaprine is best used in short term treatment, but may be used intermittently for chronic pain. Antidepressants, neuroleptics, anticonvulsants and some other drugs can be used long term. Topical analgesic agents may also be used.     

Neuropeptides in human memory and learning processes

The neuropeptides vasopressin, adrenocorticotropin (ACTH), and beta-endorphin seem to have important effects on memory and learning. Animal studies attempting to demonstrate these effects are difficult to interpret because of the complexity of behavior that is described as "learning" and the impossibility of assessing verbal learning in animals. This article therefore reviews some of the animal literature on neuropeptides and learning, but focuses primarily upon studies in humans, both in normal volunteers and in patients with neurological disorders. Vasopressin enhances learning under some conditions. Intranasal administration has been associated with improvement on psychometric tests in patients with mild Alzheimer's disease and Korsakoff's psychosis, although these findings are not uniform. It improves performance on memory tests in normal volunteers, but does not seem to improve the memory deficit after head trauma. Cerebrospinal fluid levels are low in patients with Alzheimer's disease. ACTH and melanocyte-stimulating hormone (MSH) are two peptides the primary behavioral effect of which seems to be on attention or goal-motivated behavior rather than on memory processes themselves. Visual discrimination and the ability to continue repetitive tasks are enhanced; in mentally retarded subjects, the administration of ACTH or MSH improves performance on a variety of neuropsychological tests. It does not, however, improve cognitive function in the elderly. Endogenous opioids including beta-endorphin and met-enkephalin seem to have primarily an amnesic effect in animal studies. Their role in human learning is still uncertain, although naloxone, which antagonizes their effects, has been associated with improved cognitive performance in patients with Alzheimer's disease. These data underscore the complexity of the processes associated with human memory and the rudimentary state of our present knowledge. Whatever the mechanisms, however, vasopressin, ACTH, and endogenous opioids seem to have important effects upon memory.     

Sugar solution analgesia: the effects of glucose on expressed mu opioid receptors

Glucose or sucrose solutions administered orally provide effective analgesia for procedural pain in neonates. Because analgesia with sugar solutions can be decreased by opioid receptor antagonists, we tested the hypothesis that glucose directly activates opioid receptors. Mu opioid receptors (MOR-1) were expressed in Xenopus oocytes, a well recognized expression system, and glucose was tested for possible agonist, antagonist, and modulatory effects on the receptor. In control experiments, 10 nM of Tyr-D-Ala-Gly-Me-Phe-Gly-ol (DAMGO), a synthetic enkephalin and specific mu agonist, activated the MOR-1, whereas 20 mM of glucose had no effect. In addition, glucose had no effect on the activation of the mu receptor by DAMGO. Finally, glucose did not modulate acute receptor desensitization induced by DAMGO. We conclude that glucose does not directly interact with MOR-1 in an in vitro expression system and that the purported interaction between glucose and the opioid system may be an indirect one, involving release of endogenous opioids.     

Are peripheral opioid antagonists the solution to opioid side effects?

Opioid medication is the mainstay of therapy for severe acute and chronic pain. Unfortunately, the side effects of these medications can affect patient comfort and safety, thus limiting their proven therapeutic potential. Whereas the main analgesic effects of opioids are centrally mediated, many of the common side effects are mediated via peripheral receptors. Novel peripheral opioid antagonists have been recently introduced that can block the peripheral actions of opioids without affecting centrally mediated analgesia. We review the clinical and experimental evidence of their efficacy in ameliorating opioid side effects and consider what further information might be useful in defining their role. IMPLICATIONS: The major analgesic effects of opioid medication are mediated within the brain and spinal cord. Many of the side effects of opioids are caused by activation of receptors outside these areas. Recently developed peripherally restricted opioid antagonists have the ability to block many opioid side effects without affecting analgesia.     

Minimal immunoreactive plasma beta-endorphin and decrease of cortisol at standard analgesia or different acupuncture techniques

BACKGROUND AND OBJECTIVE: Acupuncture has been claimed to be associated with activation of the endogenous antinociceptive system. The analgesic effects of acupuncture have been ascribed to beta-endorphin interacting with opioid receptors. However, firstly, the release of beta-endorphin into the blood has been proven to be induced by stress, i.e. under dysphoric conditions, and, secondly, if released under stress, beta-endorphin has been shown not to be analgesic. Our aim was to test whether beta-endorphin immunoreactive material is released into the cardiovascular compartment during acupuncture comparing the most frequently used types of acupuncture with standard pain treatment under apparently low stress conditions. METHODS: This prospective study included 15 male patients suffering from chronic low back pain. beta-Endorphin immunoreactive material and cortisol were measured in the plasma of patients who underwent, in random order, therapy according to a standard pain treatment, traditional Chinese acupuncture, sham acupuncture, electro acupuncture and electro acupuncture at non-acupuncture points before, at and after the treatment. Statistical analysis was performed using two-way ANOVA with repeated measures. RESULTS: A decrease in plasma cortisol concentration measured over the five treatment protocols was highly significant (P < 0.001). The beta-endorphin immunoreactive material concentrations in plasma were minimal at all times and in all treatment conditions. The influence of treatments by various acupuncture procedures on cortisol and beta-endorphin immunoreactive material plasma concentrations over the three time points was not significantly different. CONCLUSIONS: beta-endorphin immunoreactive material in blood is not released by any type of acupuncture as tested under low stress conditions.     

Beta-endorphin in cerebrospinal fluid and serum after severe head injury

Endogenous opioids have been implicated as a cause of secondary damage after neural injury. The basis for this statement is primarily indirect evidence from studies that demonstrate neurological or physiological improvement when opiate antagonists are given. This study directly evaluates the level of the endogenous opioid beta-endorphin in 15 patients with severe head injury. Levels of immunoreactive beta-endorphin (ir-beta E) from ventricular cerebrospinal fluid (vCSF) and serum were determined less than 24 hours after trauma. No significant correlation was found with the degree of initial injury, age, sex, or either 6- or 12-month outcome. Levels of ir-beta E from vCSF were significantly lower in patients who had received intravenous administration of morphine sulfate (48.4 +/- 5.8 versus 85.9 +/- 10.1 pg/ml, P = 0.008). No correlation was found between vCSF levels of ir-beta E and elapsed time after injury. Although vCSF and serum ir-beta E were correlated (r = 0.532, P = 0.050), the latter exhibited a different profile; the mean level of serum ir-beta E was not significantly different in those patients who received morphine, and serum ir-beta E had a significant negative correlation with time after injury (r = -0.587, P = 0.03). These results do not support a relationship between acute levels of vCSF or serum ir-beta E and the degree of neurological injury or outcome after severe head trauma. This article, therefore, is a contribution to the body of literature in which the purported detrimental effect of beta-endorphin was not demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional distribution of opioidergic nerves in human and canine prostates

The regional distribution of opioidergic nerves in the juvenile and adult human prostate and in the adult canine prostate has been studied immunohistochemically using well-characterized polyclonal antisera against multiple opioid peptides. Nerves displaying immunoreactivity (ir) for the proenkephalin (PRO-ENK) derivatives met-enkephalin (ME), leuenkephalin (LE), octapeptide, and heptapeptide (ordered in decreasing frequency) were present in the dorsolateral stroma of human prostate. In canine prostate, the situation was similar, but the number of opioid-ir nerve fibers was lower than in human prostate. In both species, staining for the prodynorphin (PRO-DYN) derivatives dynorphin A and alpha-neoendorphin or staining for the pro-opiomelanocortin (POMC)-derived beta-endorphin was not visualized. In addition to their presence in nerve fibers, PRO-ENK-ir opioids (octapeptide) occurred in intrinsic ganglionic cells situated in the capsule. Octapeptide but not LE-ir fibers supplied stromal blood vessels. The periurethral region and tissue adjacent to the ejaculatory ducts appeared to be devoid of opioid-ir innervation. We conclude that endogenous opioids apparently exclusively derived from PRO-ENK may fulfill important comessenger functions in the fine regulation of prostatic stromal tonus and of local vascular perfusion.     

Endorphins in primate hemorrhagic shock: beneficial action of opiate antagonists

The endogenous opiate beta-endorphin is released concomitantly with adrenocorticotropin from the pituitary during stress. In the present study we investigated the possible involvement of opiate receptors in the cardiovascular depression associated with hypovolemic shock in the nonhuman primate. Changes in circulating levels in beta-endorphin were monitored during hemorrhagic shock in 18 female baboons. Plasma levels of beta-endorphin increased significantly during hemorrhagic shock and were significantly correlated with a decrease in cardiac output (P less than 0.05). Single bolus administration of the opiate receptor antagonist naloxone (2 or 5 mg/kg) produced a transient but significant improvement in cardiac output (P less than 0.05) and mean arterial pressure (P less than 0.05). Hemodynamic improvement was maintained with a constant infusion of naloxone. Opiate receptor blockade with the longer acting antagonist naltrexone (2 or 5 mg/kg) significantly increased mean arterial pressure (MAP; P less than 0.05), and CO (P less than 0.05), and decreased heart rate. Our results suggest that the baboon is an excellent model for the study of hemorrhagic shock and provide further evidence for endogenous opiate involvement in the cardiovascular pathophysiology of hemorrhagic shock.     

Nociceptin and the ORL1 receptor: pharmacology of a new opioid receptor

Molecular biological investigations led to the discovery of the ORL1 receptor ( opioid receptor like-1 receptor) and its endogenous ligand nociceptin. Although its sequence and structure are closely related to traditional opioid receptors, the ORL1 receptor shows low binding affinities for selective opioid agonists and antagonists. On the other hand, the ORL1 ligand nociceptin does not bind to the three traditional opioid receptors.The activation of the G protein-coupled ORL1 receptor inhibits adenlylate cyclase activity, reduces the intracellular concentration of the second messenger cAMP and regulates ion channels. The supraspinal administration of nociceptin produces hyperalgesia. unlike opioids. Spinal intrathecal and peripheral administration of nociceptin causes hyperalgesia in low doses and analgesia in high doses.The physiological role and detailed mechanisms of these dose-dependent nociceptin effects in opposite directions are not yet known.In addition, nociceptin modulates other biological phenomena such as feeding, locomotion, gastrointestinal function,memory, cardiovascular function,immunity, renal function, anxiety,dependence and tolerance.Future research on the physiological and pathophysiological importance of the nociceptin/ORL1 receptor systems may provide a target for novel therapeutics.     

Rational use of opioids

The role of analgesia and sedation in intensive care units (ICU) is ancillary to other intensive care strategies, nevertheless they permit that every other diagnostic and therapeutic procedure is safely performed by keeping the patient pain-free, anxiety-free and cooperative. Commonly used opioids in ICU include morphine, fentanyl, sufentanil and remifentanil. The choice among opioid drugs relies on their pharmacokinetics and their pharmacodynamic effects. Cardiovascular stability observed with fentanyl and sufentanil indicates their use in hemodynamically compromised patients. Short-acting remifentanil offers several advantages in patients requiring prolonged infusions. The organ-independent metabolism of this newer molecule may be valuable in patients with multiple organ failure. The main indications for opioid analgesia and sedation in ICU include: 1) Anxiety, pain and agitation: in turn, they can increase cardiac workload, myocardial oxygen consumption and rate of dysarrhythmias; 2) immediate postoperative period after major surgery; 3) short-term invasive procedures. Potential advantages offered by opioids in the ICU setting also include: a) Cardiac protection: in animal models, it has been observed that delta-opiate receptor stimulation confers a preconditioning-like protective effects against myocardial ischemia; b) Neuroprotection: recent studies suggest that mu- and kappa-opiate receptors are involved in ischemic preconditioning against seizures in the brain. During opioid therapy in the ICU, drug tolerance and withdrawal symptoms should be anticipated and the dose adjusted accordingly.     

Use of dalargin in complex anesthesiological protection during operations on the abdominal organs

The authors analyse experience in the use of the synthetic analogue of ++leu enkephalin dalargin in multicomponent balanced anesthesia in operations on the abdominal organs in 36 patients. With the use of the suggested method the intraoperative expenditure of narcotic analgesics is 6 times less but the efficacy of the anesthesia remains the same. Study of the activity of the liver-specific enzymes (histidase and urokinase) in blood plasma and biopsy material taken from the liver and the content of malonic dialdehyde in the hepatic biopsy specimen revealed hepatoprotective properties of dalargin. The decrease of the total peripheral resistance and increase of the elasticity of the arterial reservoir++ in the main group as compared to these values in patients treated by the traditional method were considered by the authors to be the consequence of the autonomic priming effect of the opiopeptide used. It is concluded that the use of synthetic analogues of endogenous opioids (dalargin) in the anesthesiological protection complex in operations on the abdominal organs is expedient.     

Opioid peptides and receptors in joint tissues: study in the rat.

Using immunohistochemical and biochemical techniques, the occurrence of endogenous opioid peptides and their receptors in normal rat bone and joint tissues was investigated. Opioid receptors were detected, quantified, and characterized in homogenates from capsule/synovium and periosteum using radioligand binding assays. Receptor binding of the nonselective opioid [3H]naloxone to tissue homogenates was stereospecific and saturable, showing similar characteristics to that of brain tissue, although with lower binding capacities. By immunohistochemistry, the neuronal occurrence of four different enkephalins was demonstrated in synovium, bone marrow, periosteum, and juxta-articular bone, whereas no neuronal dynorphin immunoreactivity was detected. Double-staining studies disclosed that enkephalins coexisted with substance P in primary afferent fibers. The applied techniques can be used to assess changes in the distribution of endogenous opioids and their receptors in joint tissues in conditions associated with pain and inflammation. The endogenous opioid system now demonstrated might be targeted and exploited therapeutically to obtain peripheral control of symptoms in joint disorders.     

Plasma beta-endorphin and beta-lipotropin in patients with end-stage renal disease--effects of hemodialysis

The effect of hemodialysis on the plasma concentration of beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) was studied in 11 patients with end-stage renal disease (ESRD). The plasma beta-EP/beta-LPH concentrations measured at 13.00 h were not significantly different in the patients compared to age-matched controls. Furthermore, hemodialysis produced no change in the plasma concentrations of beta-EP/beta-LPH. The elevated levels of beta-EP/LPH previously reported are most likely a reflection of the measurement of these peptides at a time of peak diurnal secretion compounded by a fall in the metabolic clearance rate of the endogenous opioids in ESRD. It remains to be established whether measurement of adronocorticotropic hormone or beta-EP/beta-LPH is more accurate an indicator of the integrity of the hypothalamic-pituitary-adrenal axis in patients with ESRD.     

Molecular biology of adrenergic and dopamine receptors and the study of developmental nephrology

Neurotransmitters convey specific messages by binding to receptors on the cell membrane surface. Receptors are linked to membrane-bound, signal-transducing proteins which act as intermediaries in the generation of second messengers that elicit biological responses. Cell surface receptors could be grouped into families that utilize common systems for their signal transmission. These classes include the growth factor receptors, the transporter receptors which internalize their ligands, ion channels, and G-protein-coupled receptors. In the past few years, the cDNAs and/or genes of a number of G-protein-coupled receptors have been cloned. Structural analysis of the G-protein-coupled receptors, as well as the other classes of receptor, shows that those receptors which use a common signaling pathway have similar topographies and share significant sequence homology. Adrenergic and dopamine receptors are examples of receptors coupled to G proteins. This review outlines some strategies in the study of adrenergic and dopamine receptors using molecular biology techniques and how they relate to investigations in developmental nephrology.