Opioid Substance Research Articles

Pharmacological characterization of the binding of [3H]bremazocine in guinea-pig brain: evidence for multiplicity of the κ-opioid receptors

In guinea-pig brain, [3H]bremazocine has a binding capacity of 27.2 pmol/g wet tissue, which is statistically different from that of [3H]ethylketazocine (14.7 pmol/g wet tissue) or the sum of the individual binding capacities of mu-, delta-, and kappa-selective ligands (15.0 pmol/g wet tissue). Saturation studies of [3H]bremazocine performed in the presence of unlabelled mu-, delta-, and kappa-blockers still reveal a homogeneous population of binding sites. [3H]Bremazocine under suppressed conditions displays at these sites a Kd of 2.51 nM with a binding capacity of 9.15 pmol/g wet tissue. We have performed the pharmacological characterization of these additional opioid binding sites. Displacement curves measured with a number of opioid substances were all best fitted to a one-site model. The stereoselectivity of these additional sites was demonstrated by using two groups of stereoisomers. Oripavine and benzomorphan opioids were among the most potent drugs at the [3H]bremazocine sites (mu + delta + kappa suppressed). Diprenorphine, bremazocine, cyclazocine, and ethylketazocine displayed apparent affinities constants (1/Ka) of 8.66, 7.57, 21.4, and 38.0 nM, respectively at those sites. The kappa-selective drugs U50488, U69593, PD117302, and tifluadom were inhibitors of the binding of [3H]bremazocine at these sites with apparent affinities of 113, 268, 76.9, and 47.9 nM. All mu- or delta-selective drugs tested in this study have caused weak or no inhibition of the binding. Correlation analyses were done between the different affinities measured at the [3H]bremazocine sites (mu + delta + kappa suppressed) and those observed at the known mu-, delta-, and kappa-sites of the guinea-pig brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of morphine and naloxone on feline colonic transit

The effects of endogenous and exogenous opioid substances on feline colonic transit were evaluated using colonic transit scintigraphy. Naloxone (0.3 mg/kg, i.m.) accelerated emptying of the cecum and ascending colon, and filling of the transverse colon. Endogenous opioid peptides thus appear to play a significant role in the regulation of colonic transit. At a moderate dose of morphine (0.1 mg/kg, i.m.), cerum and ascending colon transit was accelerated, while at a larger dose (1.0 mg/kg, i.m.) morphine had no effect. Since naloxone, a relatively nonspecific opioid antagonist, and morphine, a principally mu opioid receptor agonist, both accelerate proximal colonic transit, a decelerating role for at least one of the other opioid receptors is inferred.

Opposite effects of κ-opioid agonists on gastric emptying of liquids and solids in dogs

The influence of oral (p.o.) administration of κ-(U-50488, tifluadom) and μ- (morphine, DAGO) opioid substances on gastric emptying of liquids and solids in a standard canned dog food meal was evaluated using a double-radiolabeled technique in dogs fitted with gastric cannulas. One hour after feeding, 28.6% ± 3.6% (mean ± SD) of the solid phase and 27.1% ± 8.6% of the liquid phase of the meal had been emptied. Both U-50488 and tifluadom given orally (0.01–0.1 mg/kg) significantly increased (p < 0.05) the 1-h emptying of the solid phase of the meal by 23.1%–49.6%. In contrast, both drugs significantly reduced emptying of liquids. These effects were not reproduced when similar doses were given intravenously. Oral administration of morphine or DAGO (0.01–0.1 mg/kg) did not affect gastric emptying, whereas an inhibited emptying of solids was observed for morphine at a higher dose (1 mg/kg p.o.). At a dose of 100 μg/kg i.v. both naloxone and MR 2266 (0.1 mg/kg) abolished the effects of orally administered U-50488 on gastric emptying of solids and liquids. It is concluded that κ- but not μ-agonists act locally to alter gastric emptying of a standard meal in dogs, having opposite effects on solid and liquid phases. A selective local stimulation of κ mucosal or submucosal receptors of the gastroduodenal area may explain such effects.

Peripheral antagonistic action of trimebutine and κ opioid substances on acoustic stress-induced gastric motor inhibition in dogs

The effects of intracerebroventricular (i.c.v.), intravenous and (i.v.) and oral (p.o.) administration of trimebutine on the gastric motor inhibition induced by acoustic stress were investigated in fasted dogs fitted with strain-gauge transducers on the antrum and proximal jejunum. Started 40–50 min after the last migrating motor complex, a 1 h acoustic stress delayed by 111% the occurrence of the next gastric migrating motor complex without affecting the jejunal motor pattern. This inhibition of gastric migrating motor complex induced by acoustic stress was abolished by previous p.o. administration of trimebutine (1 mg/kg) but not by its i.v. (0.1 mg/kg) or i.c.v. (0.01 mg/kg) injection. The trimebutine blockade of gastric motor alterations induced by acoustic stress was suppressed after previous i.v. treatment with MR 2266 (0.3 mg/kg) but was unaffected by naloxone (0.3 mg/kg). Furthermore oral administration of U-50488H (10 μg/kg) and ethylketocyclazocine (10 μg/kg) respectively abolished and reduced the acoustic stress-induced delay of the occurrence of the gastric migrating motor complex. We concluded that trimebutine is able to antagonize the gastric motor disturbances induced in dogs by acoustic stress, probably by acting selectively on peripheral κ receptors located in the wall of the proximal gut and directly stimulated from a mucosal site.

Effect of bone marrow opioid peptides on antibody formation in the productive phase of the immune response

The cells of intact spinal cord produce a group of biologically active peptides--myelopeptides (MP) stimulating antibody formation at peak of immune response and exerting an analgesic endorphin-like effect. The experiments on comparative studies of antibody-stimulating effect of synthetic opioid peptides and MP have shown that the mixture of opioid substances composed in aliquots corresponding to their content in MP has an antibody-stimulating effect similar to that of MP. Synthetic beta-endorphin also enhances the antibody formation during the productive phase of immune response at doses 1000-fold lower than its MP level. Leu- and met-enkephalins have no antibody-stimulating effect. An antagonist opiate, naloxone, blocks the antibody-stimulating activity of both opiates and MP. A close correlation between antibody-stimulating and analgetic endorphin-like MP activity has been established.

Hypothalamo-pituitary-interrenal responses to opioid substances in the trout: II. Effects of morphine and d-Ala 2, Met 5-enkephalinamide on plasma cortisol titres in vivo

The influence of morphine, d-Ala 2, Met 5-enkephalinamide (DALA), and naloxone on plasma cortisol titres has been studied in vivo in fingerling and adult trout. The responses were complex and variable. A single ip injection of morphine or DALA into fingerlings usually resulted in a rise in plasma cortisol after 0.5 hr followed by a fall below control values within 2 hr. In similar experiments with adult trout, only an inhibitory effect was observed. Naloxone reduced the rise in plasma cortisol following saline injection, but only when the hypothalamo-pituitary-interrenal response was intense. The antagonist also blocked the morphine-induced rise in cortisol secretion. Prolonged morphine treatment diminished both the postinjection and stress-induced secretion of cortisol in adult fish. Morphine had no effect on the spontaneous or ACTH-induced secretion of cortisol by interrenal tissue incubated in vitro. The results support the concept of inhibitory and stimulatory sites of action by opiates and opioid substances on the hypothalamo-pituitary-interrenal axis. These findings are discussed with reference to the action of morphine on hypothalamic and pituitary tissue of the trout in vitro and with the opioid control of hypothalamo-pituitary-adrenal function in mammals.

Hypothalamo-pituitary-interrenal responses to opioid substances in the trout: I. Effects of morphine on the release in vitro of corticotrophin-releasing activity from the hypothalamus and corticotrophin from the pituitary gland

The effects of morphine and naloxone on the secretion in vitro of corticotrophin (ACTH) and and corticotrophin-releasing factor (CRF) by the pars distalis and hypothalamus, respectively, have been studied in the trout. The spontaneous in vitro secretion of corticotrophin by the pars distalis is depressed significantly by the addition of high concentrations of morphine (10 −6–10 −7 mol/litre) to the incubation medium. The effect is naloxone reversible. Morphine does not influence the response of the pituitary tissue to exogenous CRF 41, suggesting that the inhibitory influence of the opiate is exerted primarily on the CRF nerve terminals within the pars distalis and not on the corticotrophs. At considerably lower concentrations (10 −10–10 −8 mol/litre) morphine stimulates the release of CRF from the isolated trout hypothalamus in vitro. Its effects are dose-dependent and antagonized by naloxone. The results suggest that two anatomically and pharmacologically distinct populations of opioid receptors mediate opposing actions of morphine on the hypothalamo-pituitary-corticotrophic system in the trout.

Antiaversive properties of opioids in the conditioned taste aversion test in rat

The antiaversive effect of μ-, κ- and δ-opioid receptor agonists conditioned taste aversion (CTA) induced by apomorphine, lithium chloride and copper sulphate in the rat was studied, in order to evaluate whether prevention of CTA is a suitable model for the study of antiemetics. Anti-aversion was not a general characteristic of all opioid substances tested. Only one dose of the μ-agonist morphine and only one dose of the κ-agonist ethylketocyclazocine had a consistent antiaversive effect against CTA induced by apomorphine; one dose of the δ-agonist [D-Ala 2, Met 5]enkephalinamide antagonized the aversion induced by lithium chloride. As the results do not correspond to our previous findings on the antiemetic effects of these opioids in the dog (all μ- and κ-agonists tested having an antiemetic effect), we conclude that the CTA test cannot be used as a screening test for potentially antiemetic drugs.

The presence of enkephalin-like substances in the eyestalk and brain of the land crab Gecarcinus lateralis.

The eyestalk of the land crab, Gecarcinus lateralis, is rich in Met-enkephalin-like materials. Leu-enkephalin, if present, is at a level which is below the sensitivity of our assay. The brain (cerebral ganglion) of this organism contains both Met- and Leu-enkephalin-like materials. Material which was reactive with our Met-enkephalin antibody was also detected in a peak that migrated after Leu-enkephalin. This biochemical study confirms earlier immunohistochemical reports which indicated that opioid substances are present in crustaceans. It also strongly supports the concept that opioid mechanisms are a product of early evolution and further demonstrates that the sequence of the smaller opioid compounds has been conserved.

Plasma Met-Enkephalin and Leu-Enkephalin in Chronic Renal Failure

Plasma met-enkephalin and leu-enkephalin has been measured in a group of 28 patients with chronic renal failure, to discover whether these opioids are affected by standard haemodialysis and haemofiltration. Met-enkephalin was markedly higher (P less than 0.001) in uraemic patients than in a group of 13 normal subjects, and was directly related to plasma creatinine (r = 0.60; P less than 0.01) and to plasma urea (r = 0.36; P = 0.06). In contrast, leu-enkephalin was suppressed in uraemic patients (P less than 0.001). Met-enkephalin fell slightly but significantly (P less than 0.02) after both haemodialysis and haemofiltration; however, on average it remained at concentrations four times higher than normal. No changes in plasma leu-enkephalin were observed after haemodialysis and haemofiltration. The cause(s) of the altered plasma concentrations of these opioid substances remains to be clarified.

Interrelationships of Opioidergic and Adrenergic Mechanisms Controlling the Secretion of Corticotrophin Releasing Factor in the Rat

The effects of morphine and naloxone on hypothalamo-pituitary-adrenocortical (HPA) activity and blood pressure were studied in rats in which adrenergic transmission had been impaired pharmacologically. The alpha 1-adrenoceptor antagonist, prazosin and the tyrosine hydroxylase inhibitor, alpha-methyl-para-tyrosine (alpha-MPT), increased the hypothalamic corticotrophin releasing factor (CRF) content and the plasma corticotrophin (ACTH) concentration and exaggerated the HPA response to stress. In addition, the spontaneous secretion of CRF by hypothalami in vitro was increased by alpha-MPT-treatment. Morphine enhanced the basal and stress-induced activity of the HPA system in vivo. It also stimulated the secretion of CRF by hypothalami in vitro. Naloxone did not affect resting HPA activity but reduced markedly the stress-induced release of corticotrophin. The effects of morphine and naloxone on the HPA axis, in vivo, were reduced by pretreatment with alpha-MPT and prazosin, respectively. The HPA responses could not be correlated with the changes in blood pressure which the drugs caused. The results suggest that opioid substances stimulate HPA activity by depressing the activity of the adrenergic pathways which inhibit the secretion of CRF.

Antinociceptive profile of sulfated CCK-8: Comparison with CCK-4, unsulfated CCK-8 and other neuropeptides

The antinociceptive activity of sulfated cholecystokinin octapeptide (CCK-8-S) was characterized by comparison with two other endogenous forms, unsulfated CCK-8 (CCK-8-U) and the carboxyl tetrapeptidc fragment (CCK-4) and two other peptides present m the gut and brain: bombcsin and neurotensin. By the intracerebroventricular (i.c.v.) route, CCK-8-S was antinociceptive in the hot plate and phenylquinone-induced writhing assays, but CCK-8-U and CCK-4 were active only in the latter test. By systemic administration, CCK-8-S retained anti-writhing activity but CCK-8-U and CCK-4 did not. Therefore, CCK receptors in brain may be involved in the apparent antinociception produced by CCK-8-U and CCK-4. Bombesin produced potent antinociceptive activity, along with a distinct, head-scratching syndrome, in both the writhing and hot plate tests. Naloxone reversed bombesin-induced elevation of latencies of mouse jump but not the head-scratching syndrome, indicating that the analgesic effect in the hot plate test was independent of the scratching behaviour. Neurotensin, unlike CCK-8-S, elevated tail-flick latencies, and was more potent in the writhing than in the hot plate test. Several differences between CCK-8-S and opioid substances included the need for relatively large doses of naloxone to block the effects of CCK-8-S in the phenylquinone-induced writhing test and the lack of effect of CCK-8-S in the tail-flick test. Global sedation can account for some, but not all, of the effects of CCK-8-S. Despite previous suggestions that CCK-8-S has opiate antagonist properties, the present results and clinical reports suggest that this neuropeptide may possess clinically-relevant analgesic properties.

Cardiovascular and endocrine effects of naloxone compared in normotensive and hypertensive patients

Naloxone, a competitive antagonist of opioid receptors, and placebo (dextrose 5% in water (D5W)) were administered on separate days to healthy normotensive (NT) male volunteers and to male patients with essential hypertension (HT). A single-blind, placebo-controlled, cross-over design was employed. Increasing doses of naloxone (0.4, 1.2, 3.6, 10.8, 32.4, 97.2 mg) were given every 30 min as slow i.v. boluses. On a separate day, i.v. boluses of D5W were given according to a similar protocol. Naloxone failed to significantly modify systolic and diastolic blood pressure (BP), heart rate (HR), respiratory rate, oral temperature or plasma catecholamines. No adverse reactions or behavioral effects were seen with naloxone. Naloxone produced a dose-dependent increase in plasma cortisol, whereas plasma cortisol showed a gradual decline on the placebo day (circadian variation). HT and NT showed similar maximal increases in plasma cortisol. Hypertensives responded to lower doses of naloxone with greater increases in plasma cortisol. The results were significantly different only if corrected by using the baseline values obtained on the placebo day. The study suggests that in awake, resting men, endogenous opioids play no role in regulating BP, HR, respiration, temperature or the activity of the sympathetic nervous system. It also suggests that the sustained elevation of BP in HT is not due to endogenous opioid substances. However, endogenous opioid substances produce a tonic inhibitory effect on the release of cortisol. This tonic inhibition seems to be greater in hypertensives than in normotensives.

The olfactory tubercle of the cat II. Immunohistochemical compartmentation

In this study immunohistochemistry is used to investigate the distribution of opioid peptides, substance P (SP), neuropeptide Y (NPY) and acetylcholine (ChAT) in the olfactory tubercle (OT) of the cat. On the basis of our histochemical findings we divide the OT into two parts: the cortical part and the cap regions, the latter containing the granule cell islands. The cortical part shows an intensely ir-punctate staining pattern (opioid and SP), similar to that observed in the striatum, to which it is connected via plexus bridges. The pyramidal neurons representing the main cell type of the cortical part are ir-negative. NPY-ir neurons invade the OT via the plexus bridges from the striatum and are restricted to the cortical part. A different staining pattern exists in the cap regions: dwarf and small pyramidal-like cells display opioid- and SP-like immunoreactivity and therefore are clearly separated from the cortical part. The intensely stained axonal plexus of the cap-region neurons occupies the hilus regions dorsal to the granule islands. In addition, dendrites of large pallidal neurons densely enmeshed in opioid- and SP-ir fibers (woolly fibers) enter the OT from the dorsally located ventral pallidum, pass through the hilus, traverse the granule islands and reach the dwarf cell layer, where the ir-axons apparently terminate. The granule islands do not receive ir-terminals and the granule cells are ir-negative, except some SP-positive granules in the medial islands. Within the hilus regions some large neurons are ChAT-positive, but the majority is ir-negative. The hilus neurons are regarded as the main target of the cap region efferent system. The findings of this study parallel and confirm our morphological observations (Meyer and Wahle 1986).

Opioid-hallucinogen interactions

Before the advent of neuroleptics, opioids such as morphine were used occasionally in the treatment of schizophrenia and other mental disorders. Recent interest in the possible therapeutic role of endogenous opioid peptides in various mental states has prompted a new look at the opioids. The present paper summarizes the research to date in the author's laboratory on opioid-hallucinogen interactions. A model behavioral state was induced in rats with N,N-dimethyltryptamine (DMT) or lysergic acid diethylamide-25 (LSD). Several mu opioid agonists, antagonists, and synthetic enkephalin analogs interacted with DMT and LSD. Adult male Holtzman rats trained on a positive reinforcement fixed ratio four (FR 4) behavioral schedule (i.e., a reward of 0.01 ml sugar-sweetened milk was earned on every fourth bar press) were used in these studies. DMT (3.2 and 10.0 mg/kg) given with a 0.9% NaCl pretreatment IP, disrupted established food rewarded FR 4 bar pressing behavior in a dose related fashion. Pre-determined behaviorally ineffective doses of mu opioid agonists showed selective biphasic effects against DMT and LSD. Low doses antagonized the effects of both hallucinogens, whereas larger doses enhanced their effects. In contrast to the antagonistic effects of low doses of mu opioid agonists, the mu-kappa opioid antagonist (−)-naloxone enhanced the effects of DMT and LS. (−)-Naloxone enhanced the effects of DMT and LSD. Potentiation of DMT-induced behavioral disruption was attributed to a stereospecific opioid antagonist effect of (−)-naloxone in that the (+)-naloxone enantiomer failed to potentiate the effects of DMT. Further studies are indicated to determine hallucinogen-opioid interactions in various species, including man. The present findings reinforce a possible antagonist role of opioid substances in mental processes involving hallucinations.

Stimulation and inhibition of corticotrophin releasing factor secretion by beta endorphin.

The influence of beta-endorphin on the secretion of corticotrophin releasing factor (CRF) by isolated rat hypothalami in vitro was studied. beta-Endorphin (10(-11)-10(-10) M) caused dose-related increases in the CRF contents of the hypothalami and of the medium in which they were incubated. Its effects were antagonized by naloxone (10(-8)-10(-7) M). In contrast, in higher concentrations (10(-7) - 10(-5) M), it reduced, in a dose-dependent manner, both the spontaneous release of CRF from the hypothalami and the release which normally occurred in response to acetylcholine, 5-hydroxytryptamine, morphine, met-enkephalin and leu-enkephalin. The inhibition of CRF release was associated with a rise in the tissue content of the hormone and was not blocked readily by naloxone. The results support the concept that opioid substances may be involved in the control of hypothalamo-pituitary-adrenocortical function.

Naltrexone antagonizes the biobehavioral adaptation to cold water stress in rats

The reported studies on the development of tolerance to the analgesic effects of stress have been mostly concerned with the involvement of opioid or non-opioid substances in stress-induced analgesia (SIA). To further investigate the processes involved in SIA tolerance, rats were exposed to forced intermittent cold water swim (ICWS, 18 exposures, 3/min, 10 sec each) on 16 consecutive days. On days 15 and 16, they were injected prior to swim with saline and naltrexone (10 mg/kg), respectively. During swim, three types of readily identifiable behaviors were observed. They may be characterized by immobility and horizontal floating (Type I), intensive activity and escape attemps (Type II), and passivity and “behavioral despair” (Type III). In the acute condition, only Type II and Type III appear in sequence. In the chronic condition, the sequence of behaviors is: Type I, Type II, and Type III. Thirty minutes after swim, analgesia, core temperature, and degree of inactivity were measured. With chronic exposure, tolerance developed to the analgesia, core hypothermia and hypoactivity induced by the ICWS. Type I behavior appeared on day 3 or 4 persisted throughout the chronic treatment. Type II behavior did not adapt. Naltrexone (10 mg/kg) antagonized the adaptive aspect of all those variables where adaptation or tolerance were found (analgesia, hypoactivity, core hypothermia, and Type I behavior) but had no effect on Type II behavior where no adaptation was observed. It is suggested that the endorphins have a functional role in the behavioral and physiological adaptation to aversive stressful environmental situations.

Subject index volume 14 (1984/1985)

The prevalence of chronic pain, including but not limited to back, leg, and pelvic pain, is substantial during the peripartum period. Such pain may affect maternal and fetal outcomes. Therefore, obstetric anesthesiologists should be familiar with the analgesia provided to patients with chronic pain as well as any history of opioid dependence or substance abuse. We systematically searched PubMed and the Cochrane databases for all reports published on perioperative management of parturients with chronic pain. Abrupt cessation of opioid maintenance treatment or the use of partial opioid agonists-antagonists (commonly prescribed to parturients) is likely to cause acute withdrawal and uncontrolled pain that could lead to preterm labor, fetal abnormalities, or even fetal demise. Parturients receiving opioid maintenance therapy typically require higher doses of opioids for pain relief because they have a lower pain threshold. However, complying with such requests for higher doses may further compromise patient, fetus, and neonate safety. Opioid agonist-antagonist drugs, except buprenorphine, should be avoided in patients receiving maintenance opioid therapy. Drugs such as nalbuphine, butorphanol, pentazocine, and tramadol may incite severe withdrawal. Similarly, buprenorphine should not be offered for acute pain management to a parturient who is receiving methadone maintenance. Individualized plans of prenatal and neonatal care as well as breastfeeding are important during hospital admission of those dependent on opioids. Parturients who have implanted pain management devices such as spinal cord stimulators (SCSs) or intrathecal pumps (ITPs) should receive particular attention from anesthesiologists. Localizing the SCS lead or the ITP catheter positions is essential for safe administration of axial analgesia. Fluoroscopic images of the SCS leads and ITP catheters obtained during implantation are routinely available and should be acquired to avoid damage to these leads. Ultrasonography may be used for mapping the lead or catheter if fluoroscopic images cannot be obtained. The substantial prevalence of chronic pain in the obstetric population suggests the need for further research. Investigations should focus on gaining a better understanding of chronic pain during pregnancy, labor, and delivery so as to develop effective anesthetic and analgesic strategies.

Inhibition of primate spinothalamic tract cells by TENS.

Transcutaneous electrical nerve stimulation (TENS) was applied in an experimental animal model to investigate the underlying mechanisms of this treatment. Recordings were made from identified spinothalamic tract (STT) neurons in the lumbosacral spinal cords of seven anesthetized monkeys. The STT cells were activated by stimulating the common peroneal nerve at a suprathreshold intensity for C-fibers. Evoked responses of C-fibers were compared before, during, and after application of TENS for 5 minutes from a commercially available TENS unit. The current delivered by the TENS unit was monitored. In 14 STT cells, some degree of inhibition of C-fiber evoked responses occurred only when the intensity of TENS exceeded the threshold of A delta fibers. At a given stimulus intensity, bursts of pulses repeated at a low rate were more effective than high-rate pulses. When TENS was applied to an area of the skin within a cell's receptive field, it was more effective than when it was applied outside the receptive field. The C-fiber volley recorded from a peripheral nerve was not reduced in size, and there were no substantial changes in its latency due to TENS. The inhibition of the activity of STT cells was not altered appreciably after intravenous injection of naloxone hydrochloride. These results suggest that TENS produces central nervous system inhibition by activating A delta afferent fibers. The inhibitory effects of TENS on STT cells appear to be due to a mechanism that does not involve release of endogenous opioid substances.

Neurophysiology of Pain and Pain Modulation

An endogenous central nervous system pain-modulating network, with links in the mid brain, medulla, and spinal cord, has recently been discovered. This system produces analgesia by interfering with afferent transmission of neural messages produced by intense stimuli. Although other neurotransmitters are involved, the analgesia produced by this system depends on the release of endogenous opioid substances, generically referred to as endorphins. The system is set in motion by clinically significant pain--such as that resulting from bony fractures or postoperative pain. The analgesia network monitors the pain and controls it at the level of the spinal cord. Complex psychologic factors play an important role in the variability of perceived pain, partly because of their ability to trigger this pain-suppressing system. For example, this system contributes to the analgesic potency of placebo administration and is also activated by stress. Knowledge of this analgesia system has greatly expanded our understanding of the mechanisms underlying pain management. Opiates, like morphine and meperidine, produce analgesia by mimicking the action of endorphins in the pain. Tricyclic drugs may produce analgesia by enhancing the nonendorphin links of the same system. Future research on this system will provide new insights and, consequently, new approaches to the management of pain.