Peripheral and Spinal Actions of Opioids in the Blockade of the Autonomic Response Evoked by Compression of the Inflamed Knee Joint

Background: Three types of opioid receptors, micro, delta, and kappa, are present in the periphery and in the central nervous system. In contrast to the effects in the central nervous system, the antinociceptive action of opioids in the periphery is not as well characterized. The effects of intraarticular, spinal, and intramuscular injections of micro, delta, and kappa opioid agonists on the autonomic response evoked by compression of an inflamed knee joint were evaluated.

Methods: In halothane-anesthetized rats, arthritis was induced by injecting kaolin and carrageenan into the right knee joint. Standardized compression of the knee joint by inflation of a pediatric blood pressure cuff to 200 mmHg for 2 min produced a reliable stimulus-dependent hypertension (Delta = 13 mmHg). Drugs were delivered intramuscularly, intrathecally through a chronic catheter, or intraarticularly into the right knee joint. The drug injection was performed 4 hr after induction of the inflammation.

Results: The intrathecal administration of micro, delta, and kappa agonists resulted in a dose-dependent blockade of the cuff-evoked increase in blood pressure. The order of intrathecal drug activity on the compression-evoked blood pressure responses with median effective dose (ED50) was sufentanil (0.02 nmol; micro) > PD117302 (0.5 nmol; kappa); spiradoline (1.5 nmol; kappa) morphine (2.4 nmol; micro) > DADL (15 nmol; delta); DPDPE (18 nmol; delta) > U-50,488H (620 nmol; kappa) > naloxone = 0. The intraarticular administration of micro and kappa, but not delta agonists, produced a dose-dependent blockade of a compression-evoked increase in blood pressure, with the order of drug activity (ED50) as follows: sufentanil (0.04 micro mol) > PD117302 (0.3 micro mol); spiradoline (0.8 micro mol), morphine (0.9 micro mol) > U-50,488H (0.9 micro mol) > DPDPE (> 5 micro mol); DADL (> 18 micro mol) > naloxone = 0. Intramuscular injection of these agonists caused suppression, with the order of drug activity (ED50) as follows: sufentanil (0.2 micro mol) > PD117302 (2 micro mol); spiradoline (11 micro mol) morphine (9 micro mol) > DPDPE (> 5 micro mol); DADL (18 micro mol) > U-50,488H (22 micro mol) > naloxone = 0. All intraarticular effects were reversible by injecting naloxone intramuscularly, with the ordering of naloxone potency against equiactive doses of morphine > U50,488H.     

Sufentanil, morphine, met-enkephalin, and kappa-agonist (U-50,488H) inhibit substance P release from primary sensory neurons: a model for presynaptic spinal opioid actions

An in vitro model system for analysis of presynaptic inhibitory actions of spinal opioids has been applied. Embryonic sensory neurons derived from chick dorsal root ganglia were grown in primary cell culture, and the release of substance P was evoked by electrical field stimulation during exposure to drugs with well-demonstrated affinity for opioid receptors. This allowed a pharmacologic characterization of the inhibitory actions of specific opioid agonists on the release of substance P as measured by radioimmunoassay (RIA). Sufentanil (0.5 microM), a high affinity mu receptor agonist, U-50,488H (25 microM), a selective kappa receptor agonist, and morphine (10 microM), an agonist with high affinity for mu and delta receptors, inhibited the evoked release of substance P by approximately 60%, 40%, and 50%, respectively. For sufentanil the response was demonstrated to be dose-dependent. As is the case for its analgesic action in vivo, morphine was approximately 50-fold less potent than sufentanil on a molar basis in this assay. The actions of sufentanil, U-50-488H and morphine were mimicked by the endogenous opioid peptide met-enkephalin, and its stable synthetic analog D-ala2-met5-enkephalinamide (DAME). Naloxone (25 microM), an opioid receptor antagonist, blocked the inhibitory action of sufentanil (0.5 microM), morphine (5 microM), and DAME (5 microM), but not U-50,488H (10 microM). The action of U-50,488H was partially blocked by the antagonist naltrexone (25 microM). Stereo-selectivity of agonist action was confirmed by the failure of dextrorphan (50 microM), an inactive opioid isomer, to inhibit the release of substance P.(ABSTRACT TRUNCATED AT 250 WORDS)     

Supraspinal antinociceptive effects of mu and delta agonists involve modulation of adenosine uptake

BACKGROUND: The modulation of extracellular adenosine concentration by opioids provides evidence that the antinociceptive effects of these compounds involve endogenous adenosine. The aim of this study was to determine whether there is a relation between the inhibition of brain synaptosome adenosine uptake by opioid agonists and the analgesic effects of these compounds. METHODS: The authors used the hot plate and tail-pinch tests to evaluate in mice (C57BL/6 females; weight, 25-30 g) the effects of caffeine, a nonspecific adenosine receptor antagonist, on the antinociceptive effect induced by the intracerebroventricular administration of oxymorphone as a mu agonist, SNC80 as a delta agonist, or U69593 as a kappa agonist. They also investigated the effect of these opioid receptor agonists on the uptake of adenosine by whole brain synaptosomes. RESULTS: Caffeine decreased the analgesic effects induced by oxymorphone or SNC80 but not those induced by U69593. Oxymorphone and SNC80 inhibited adenosine uptake by brain cells, but U69593 did not. CONCLUSION: The antinociceptive effects obtained with mu or delta (but not kappa) agonists administered supraspinally were indicative of the involvement of modulation of adenosine uptake.     

Supraspinal Antinociceptive Effects of μ and δ Agonists Involve Modulation of Adenosine Uptake

Background: The modulation of extracellular adenosine concentration by opioids provides evidence that the antinociceptive effects of these compounds involve endogenous adenosine. The aim of this study was to determine whether there is a relation between the inhibition of brain synaptosome adenosine uptake by opioid agonists and the analgesic effects of these compounds.

Methods: The authors used the hot plate and tail-pinch tests to evaluate in mice (C57BL/6 females; weight, 25-30 g) the effects of caffeine, a nonspecific adenosine receptor antagonist, on the antinociceptive effect induced by the intracerebroventricular administration of oxymorphone as a [mu] agonist, SNC80 as a [delta] agonist, or U69593 as a [kappa] agonist. They also investigated the effect of these opioid receptor agonists on the uptake of adenosine by whole brain synaptosomes.

Results: Caffeine decreased the analgesic effects induced by oxymorphone or SNC80 but not those induced by U69593. Oxymorphone and SNC80 inhibited adenosine uptake by brain cells, but U69593 did not.     

Antinociception by intrathecal midazolam involves endogenous neurotransmitters acting at spinal cord delta opioid receptors

Intrathecal midazolam causes antinociception by combining with spinal cord benzodiazepine receptors. This effect is reversible with doses of naloxone, suggesting involvement of spinal kappa or delta but not micrograms opioid receptors. The antinociceptive effects of intrathecally administered drugs in the spinal cord were demonstrated by measurements of the electrical current threshold for avoidance behaviour in rats with chronically implanted lumbar intrathecal catheters. A comparison was made of suppression by two opioid selective antagonists (nor- binaltorphimine (kappa selective) and naltrindole (delta selective)) of spinal antinociception caused by equipotent doses of opioids selective for different receptor subtypes (U-50488H (kappa), DSLET and DSBULET (delta), fentanyl (micrograms)) and the benzodiazepine midazolam. Nor- binaltorphimine selectively suppressed the effects of U-50488H but not midazolam or fentanyl. However, the delta selective antagonist, naltrindole, caused dose-related suppression of antinociception produced by both delta opioid agonists and midazolam with the same ED50 (0.5 nmol). We conclude that intrathecal midazolam caused spinally mediated antinociception in rats by a mechanism involving delta opioid receptor activation.      

Opioids in anesthesia

Opioids are the most effective and widely used drugs in the treatment of severe acute and chronic pain. They act through opioid receptors that belong to the family of G protein-coupled receptors. Three classes of opioid receptors (mu, delta, kappa), expressed in the central and peripheral nervous system, have been identified. The analgesic effect of opioids is mediated through multiple pathways of opioid receptor signaling (e.g., G(i/o) coupling, cAMP inhibition, Ca(++) channel inhibition). The standard exogenous opioid analgesics used in the operating room are fentanyl, sufentanil, morphine, alfentanil, and remifentanil. Preclinical pharmacology, clinical applications, and side effects will be reviewed in this chapter.     

Assessment of the Potency and Intrinsic Activity of Systemic versus Intrathecal Opioids in Rats

Background: One measure of an opioid's efficacy is its ability to retain its analgesic effect as the intensity of a noxious stimulus is increased. A few studies have assessed the ability of either spinal or systemic opioids to produce analgesia using low- and high-intensity stimulation. There are little data available to show whether there are differences in efficacy between systemic and intrathecal opioid administration. The purpose of this study was to assess the relative efficacy of several clinically useful opioids systemically and spinally and to determine whether intrathecal administration resulted in greater efficacy than systemic administration.

Methods: Groups of rats were administered multiple doses of meperidine, morphine, hydromorphone, fentanyl, sufentanil, or buprenorphine either subcutaneously or intrathecally via implanted catheters. Noxious radiant heat was applied sequentially to each hindpaw, one at low intensity (adjusted to a mean withdrawal latency of 10 s) and one at high intensity (adjusted to a mean withdrawal latency of 5 s). Paw withdrawal latencies were recorded; dose-response curves for each intensity and each route of administration were graphically recorded, and ED50 s were calculated. Ratios of high-to low-stimulus intensity ED sub 50 s were calculated for both routes of administration for each drug, and the ratios of subcutaneous-to-intrathecal ED50 s for low-intensity stimulation were calculated to assess the relative systemic versus spinal potencies for each drug.

Results: The ratios of the high-to-low intensity ED50 s were meperidine, 11.8, morphine, 6.1, hydromorphone, 2.6, fentanyl, 2.3, sufentanil, 1.8, and buprenorphine, 24.0. For intrathecal administration, there was uniformity of the high- to low-intensity ED50 ratios for the agonist drugs (meperidine, 2.1; morphine, 2.1; hydromorphone, 1.9; fentanyl, 1.8; sufentanil, 1.6). For morphine and hydromorphone, the systemic ED50 doses were several hundred times the intrathecal ED50 s, whereas the systemic-to-spinal ED50 ratios for the other drugs were 20 or less.     

The role of drug-lipid interactions on the disposition of liposome-formulated opioid analgesics in vitro and in vivo

Although liposome encapsulation prolongs the duration of action of epidurally administered drugs, little is known about how liposome encapsulation affects opioids differently, or about how lipid content of liposomes alters the bioavailability of epidurally-administered opioids. To address these issues, morphine, alfentanil, fentanyl, and sufentanil were loaded into D-alpha-dipalmitoyl phosphatidylcholine multilamellar liposomes, and incorporation efficiency and in vitro release rates were determined. We then determined epidural morphine and sufentanil liposomes, at two different lipid/opioid ratios, in vivo in a pig model in which epidural and intrathecal spaces were continuously sampled via microdialysis. Liposome encapsulation efficiency was significantly more for sufentanil (100%) than for the other opioids (25%-30%). The in vitro release rate was slowest for morphine, intermediate for fentanyl and alfentanil, and fastest for sufentanil. In vivo, morphine was released more slowly than sufentanil. It is most important to note that increasing the lipid content of morphine liposomes increased the proportion of drug reaching the intrathecal space. In contrast, increasing the lipid content of sufentanil liposomes did not alter intrathecal movement but did decrease movement into plasma. Therefore, increasing drug hydrophobicity and lipid content of the liposomes modulates drug distribution in vivo. IMPLICATIONS: The degree of interaction between opioids and lipid bilayers in liposome-formulated opioids dictates the rates at which epidurally-administered drugs distribute into the intrathecal compartment and blood in potentiating analgesic effects.     

RELATIONSHIP BETWEEN ANALGESIA AND RESPIRATORY DEPRESSION FOR MU OPIOID RECEPTOR AGONISTS IN MICE

The relationship between analgesic activity, measured as thehot plate reaction time, and respiratory depression, measuredas ventilatory frequency, was investigated in mice for a varietyof mu opioid receptor agonists with differing selectivitiesfor mu receptors compared with delta receptors. There was aweak correlation between analgesia and respiratory depressionfor opioids with the greatest selectivity for mu opioid receptorscompared with delta receptors, such as alfentanil. The strengthof the correlation increased for opioids which had greater deltareceptor activity, such as morphine and fentanyl. Etorphine,which has almost equal affinity for mu, delta and, incidentally,kappa receptors, showed a strong correlation between analgesiaand respiratory depression. We conclude that the predictabilityof the degree of respiratory depression produced by a givenanalgesic dose of an opioid appears to decrease with its selectivityfor mu opioid receptors, at least in the mouse.     

Role Central Mu, Delta-1, and Kappa-1 Opioid Receptors in Opioid-induced Muscle Rigidity in the Rat

Background: Opioids appear to produce their physiologic effects by binding to at least three types of opioid receptors, the mu (micro), delta (delta), and kappa (kappa) receptors. Muscle rigidity occurs after administration of supra-analgesic doses of potent micro-preferring agonists like alfentanil. The role of different supraspinal opioid receptors in this rigidity has been addressed only recently. To elucidate the contribution of central micro, delta, and kappa receptors to muscle rigidity, the effects of intracerebroventricularly administered opioid receptor-selective agonists and antagonists on alfentanil-induced muscle rigidity were examined in rats.

Methods: Rats in which chronic intracerebroventricular cannulae had been implanted received an intracerebroventricular infusion of either saline or a micro (D-Ala2,N-Me-Phe4 -Gly5 -ol-enkephalin; DAMGO), delta1 (D-Pen2,D-Pen5 -enkephalin; DPDPE), or kappa1 (trans-(plus/minus)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohex yl)-benzene-acetamide methane sulfonate; U50,488H) opioid agonist. Ten minutes later, they received either saline or the micro-agonist alfentanil subcutaneously. Muscle rigidity was assessed using hindlimb electromyographic activity. Different groups of animals were pretreated with an intracerebroventricular infusion of either saline or a micro (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2; CTAP), delta (naltrindole), or kappa1 (norbinaltorphimine) opioid antagonist before administration of either saline or a selective intracerebroventricular agonist.

Results: The micro agonist DAMGO alone dose-dependently induced muscle rigidity. This effect was antagonized by pretreatment with the micro-selective antagonist CTAP. Neither DPDPE nor U50,488H, when administered alone, affected muscle tone. However, both the delta1 and kappa1 agonists dose-dependently attenuated alfentanil-induced rigidity. This antagonism of alfentanil rigidity was abolished after pretreatment with the delta (naltrindole) and kappa1 (nor-binaltorphimine) antagonists, respectively.     

Studies of the pharmacology and pathology of intrathecally administered 4-anilinopiperidine analogues and morphine in the rat and cat

In rats, intrathecal alfentanil, lofentanil, sufentanil, fentanyl, and morphine produced dose-dependent elevations in the hot-plate and tail-flick latencies and a powerful suppression of the writhing response. The slopes of the monotonic dose-response curves for the five opioids did not differ significantly. In terms of the hot-plate ED50 after intrathecal injection, the order of potency was as follows: lofentanil (210), sufentanil (29), fentanyl (3), morphine (1), and alfentanil (1). Comparable results were observed in the tail flick. The duration of action was proportional to dose. However, at doses that produced an equal magnitude of inhibition, the duration of action was lofentanil greater than morphine greater than sufentanil greater than alfentanil greater than or equal to fentanyl. Systemically administered naloxone (0.03-1 mg/kg, sc) resulted in dose-dependent antagonism of the antinociceptive effect of intrathecal morphine, fentanyl, alfentanil, and sufentanil. In contrast, intrathecal lofentanil was extremely resistant to antagonism by naloxone. In cats, similar dose-dependent blockade of the thermally evoked skin-twitch response was observed after intrathecal morphine, sufentanil, alfentanil, and fentanyl. As in the rat, the slope of the monotonic dose-response curves did not differ. The relative potency and duration of action after equipotent intrathecal doses were similar to those observed in the rodent. These results suggest that sufentanil, alfentanil, and fentanyl exert their analgesic effects in vivo at a spinal cord site that has properties comparable to those of the site acted upon by morphine. Except for catalepsy in rats, no major behavioral dysfunctions were noted at the ED50 dose of any of the drugs administered. No abnormal morphologic effects of acutely or chronically administered alfentanil and sufentanil were seen, aside from an inflammatory reaction secondary to catheter placement.     

The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance

Perioperative opioids increase postoperative pain and morphine requirement, suggesting acute opioid tolerance. Furthermore, opioids elicit N-methyl-D-aspartate (NMDA)-dependent pain hypersensitivity. We investigated postfentanyl morphine analgesic effects and the consequences of NMDA-receptor antagonist (ketamine) pretreatment. The rat nociceptive threshold was measured by the paw-pressure vocalization test. Four fentanyl boluses (every 15 min) elicited a dose-dependent (a) increase followed by an immediate decrease of the nociceptive threshold and (b) reduction of the analgesic effect of a subsequent morphine administration (5 mg/kg): -15.8%, -46.6%, -85.1% (4 x 20, 4 x 60, 4 x 100 microg/kg of fentanyl, respectively). Ketamine pretreatment (10 mg/kg) increased the fentanyl analgesic effect (4 x 60 microg/kg), suppressed the immediate hyperalgesic phase, and restored the full effect of a subsequent morphine injection. Fentanyl also elicited a delayed dose-dependent long-lasting decrease of the nociceptive threshold (days) that was prevented by a single ketamine pretreatment before fentanyl. However, a morphine administration at the end of the fentanyl effects restored the long-lasting hyperalgesia. Repeated ketamine administrations were required to obtain a complete preventive effect. Although ketamine had no analgesic effect per se at the dose used herein, our results indicate that sustained NMDA-receptor blocking could be a fruitful therapy for improving postoperative morphine effectiveness. IMPLICATIONS: Fentanyl-induced analgesia is followed by early hyperalgesia (hours), acute tolerance to the analgesic effects of morphine, and long-lasting hyperalgesia (days). All these phenomena are totally prevented by repeated administrations of the NMDA-receptor antagonist, ketamine, simultaneously with fentanyl and morphine administration.     

Opioids during anesthesia in liver and renal failure

The pharmacokinetics of opioids are impaired in patients with liver and renal failure. Fentanyl, sufentanil, and alfentanil are metabolized in the liver. The extrahepatic metabolism by renal enzymes is gaining more importance in patients with severe liver disease. Pharmacokinetic effects of single doses of fentanyl and sufentanil are not affected in liver and renal failure; however, continuous infusion of fentanyl may result in accumulation and prolonged opioid effects. Plasma clearance and elimination of alfentanil are reduced in patients with liver failure and its clinical use can therefore not be recommended. A reduction in alfentanil dosing is not necessary in patients with renal failure. Remifentanil is the opioid of choice in patients with liver and renal failure. The clearance of morphine is reduced in liver failure. In renal failure an accumulation of morphine metabolites has been demonstrated, and thus, application of morphine is not recommended in patients with liver and renal failure. A reduction in piritramide dosing is necessary in patients with liver failure.     

Epidural,cerebrospinal fluid,and plasma pharmacokinetics of epidural opioids (part 2): effect of epinephrine

BACKGROUND: The ability of epinephrine to improve the efficacy of epidurally administered drugs is assumed to result from local vasoconstriction and a consequent decrease in drug clearance. However, because drug concentration in the epidural space has never been measured, our understanding of the effect of epinephrine on epidural pharmacokinetics is incomplete. This study was designed to characterize the effect of epinephrine on the epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidurally administered opioids. METHODS: Morphine plus alfentanil, fentanyl, or sufentanil was administered epidurally with and without epinephrine (1:200,000) to pigs. Opioid concentration was subsequently measured in the epidural space, central venous plasma, and epidural venous plasma, and these data were used to calculate relevant pharmacokinetic parameters. RESULTS: The pharmacokinetic effects of epinephrine varied by opioid and by sampling site. For example, in the lumbar epidural space, epinephrine increased the mean residence time of morphine but decreased that of fentanyl and sufentanil. Epinephrine had no effect on the terminal elimination half-life of morphine in the epidural space, but it decreased that of fentanyl and sufentanil. In contrast, in the lumbar intrathecal space, epinephrine had no effect on the pharmacokinetics of alfentanil, fentanyl, or sufentanil, but it increased the area under the concentration-time curve of morphine and decreased its elimination half-life. CONCLUSIONS: The findings indicate that the effects of epinephrine on the spinal pharmacokinetics of these opioids are complex and often antithetical across compartments and opioids. In addition, the data clearly indicate that the pharmacokinetic effects of epinephrine in spinal "compartments" cannot be predicted from measurements of drug concentration in plasma, as has been assumed for decades.     

Intrathecal lipophilic opioids as adjuncts to surgical spinal anesthesia.

BACKGROUND AND OBJECTIVES: Lipophilic opioids, especially fentanyl and sufentanil, are increasingly being administered intrathecally as adjuncts to spinal anesthesia. This review analyzes the efficacy of these opioids for subarachnoid anesthesia. METHODS: Medline search of the literature from 1980 to the present and a survey of recent meeting abstracts are reviewed. RESULTS: A significant number of citations regarding intrathecal lipophilic opioids as adjuncts to spinal anesthesia were found: 59 are cited in this review. Most clinical experience has been in obstetric surgery, but lipophilic spinal opioid administration is being used with greater frequency for other surgical procedures as well. The benefits include reduction of minimal alveolar concentration (MAC) when general anesthesia is combined with spinal anesthesia and enhancement of the quality of spinal anesthesia without prolongation of motor block. Intrathecal fentanyl and sufentanil allow clinicians to use smaller doses of spinal local anesthetic, yet still provide excellent anesthesia for surgical procedures. Furthermore, lipophilic opioid/local anesthetic combination permits more rapid motor recovery; short outpatient procedures are therefore more amenable to spinal anesthesia. Finally, the side-effect profiles of intrathecal lipophilic opioids are now well characterized and appear less troublesome than intrathecal morphine. CONCLUSIONS: The anesthesia-enhancing properties and side-effect profile of lipophilic opioids administered intrathecally suggest significant roles for these agents as adjuncts to spinal anesthesia for obstetric and outpatient procedures.     

Opioide in der Anästhesie bei Leber- und Niereninsuffizienz

The pharmacokinetics of opioids are impaired in patients with liver and renal failure. Fentanyl, sufentanil, and alfentanil are metabolized in the liver. The extrahepatic metabolism by renal enzymes is gaining more importance in patients with severe liver disease. Pharmacokinetic effects of single doses of fentanyl and sufentanil are not affected in liver and renal failure; however, continuous infusion of fentanyl may result in accumulation and prolonged opioid effects. Plasma clearance and elimination of alfentanil are reduced in patients with liver failure and its clinical use can therefore not be recommended. A reduction in alfentanil dosing is not necessary in patients with renal failure. Remifentanil is the opioid of choice in patients with liver and renal failure. The clearance of morphine is reduced in liver failure. In renal failure an accumulation of morphine metabolites has been demonstrated, and thus, application of morphine is not recommended in patients with liver and renal failure. A reduction in piritramide dosing is necessary in patients with liver failure.     

Spinal sufentanil in rats: part I: epidural versus intrathecal sufentanil and morphine

Male Wistar rats were injected epidurally or intrathecally with increasing doses of sufentanil or morphine in order to determine differences in potency, onset and duration of analgesia and supra-spinal side-effects. For sufentanil, only small differences in the lowest ED50-values for analgesia and supra-spinal side-effects were observed between the two spinal routes. Given intrathecally, sufentanil had a somewhat faster onset but a shorter duration of action than did epidural sufentanil. However, intrathecal morphine when compared to epidural morphine had a faster onset with a greater potency and a longer duration of action. The stronger opioid activity of intrathecal morphine was also reflected in a reduced safety ratio for the blockade of the cornea reflex. These differences between the two opioids, with regard to their optimal route of spinal administration, are discussed in terms of lipophilicity and optimal clinical use.     

Differential effects of intrathecal midazolam on morphine-induced antinociception in the rat: role of spinal opioid receptors.

The antinociceptive effects of an intrathecally administered benzodiazepine agonist midazolam, alone and in combination with morphine, were examined in the rat by using the tail-flick test. The duration of antinociceptive effect produced by midazolam was significantly less (P less than 0.05) than that produced by morphine. Low doses of midazolam (10 micrograms) and morphine (10 micrograms) produced a synergistic effect in prolonging antinociceptive effect. However, at higher doses (20 or 30 micrograms), these drugs reduced the extent of antinociception produced by each other. Naloxone administration prevented antinociception produced by these drugs, indicating interactions between midazolam and opioid receptors. Midazolam had dual effects on the binding of opioid ligands to the spinal opioid receptors. At low dose, it potentiated the displacement of [3H]naloxone by morphine. At higher doses, midazolam inhibited the binding of opioid ligands to their spinal receptors in the following order: kappa greater than delta greater than mu. These results indicate that differential antinociceptive effects of midazolam on morphine-induced antinociception involve interaction of this benzodiazepine with spinal opioid receptors.     

Morphine, opioids, and the feline pulmonary vascular bed

Background: Opioid‐induced vasodepressor responses have been reported in a variety of species and laboratory models. The aim of this study was to ascertain the relative potencies of different clinically relevant opioids compared with traditional vasodepressor agents in the feline pulmonary vascular bed. A second aim was to study the effects of morphine and to identify the receptors involved in the mediation or the modulation of these effects. Methods: This was a prospective vehicle‐controlled study involving an intact chest preparation of adult mongrel cats. The effects of various opioids, morphine, fentanyl, remifentanil, sufentanil, and meperidine were compared with other vasodepressor agents. Additionally, the effects of l ‐N⁵‐(1‐iminoethyl) ornithine hydrochloride (l ‐NIO) (nitric oxide synthase inhibitor), nimesulide [selective cyclooxygenase (COX)‐2 inhibitor], glibenclamide (ATP‐sensitive K⁺ channel blocker), naloxone (non‐selective opioid receptor antagonist), and diphenhydramine (histamine H₁‐receptor antagonist) were investigated on pulmonary arterial responses to morphine and other selected agonists in the feline pulmonary vascular bed. The systemic pressure and lobar arterial perfusion pressure were continuously monitored, electronically averaged, and recorded. Results: In the cat pulmonary vascular bed of the isolated left lower lobe, morphine, remifentanil, fentanyl, sufentanil, and meperidine induced a dose‐dependent moderate vasodepressor response and it appeared that sufentanil was the most potent on a nanomolar basis. The effects of morphine were not significantly altered after administration of l ‐NIO, nimesulide, and glibenclamide. However, the vascular responses to morphine were significantly attenuated following administration of naloxone and diphenhydramine. Conclusion: The results of the present study suggest that sufentanil appears to have slightly more potency and morphine the least of the five opioid agonists studied on a nanomolar basis. Morphine‐induced vasodilatory responses appeared to be mediated or modulated by both opioid receptor and histamine‐receptor‐sensitive pathways.     

Respiratory effects of epidural and subcutaneous morphine, meperidine, fentanyl and sufentanil in the rat

This study compared the respiratory effects of subcutaneous and epidural morphine, meperidine, fentanyl, and sufentanil in rats breathing air or 8% CO2 in air. A whole body plethysmographic technique was used to measure minute volumes of breathing. The ED50s of subcutaneously injected morphine, meperidine, fentanyl, and sufentanil in depressing the minute volume response to 8% CO2 in air were 2300 micrograms/kg, 8800 micrograms/kg, 20 micrograms/kg, and 2.3 micrograms/kg, respectively. These doses were nearly the same as the subcutaneous ED50s of these compounds in producing analgesia, found in an earlier study. Roughly equianalgesic doses of the four opiates after epidural injection, however, failed to cause any detectable respiratory effect. Fourfold greater doses increased significantly the incidence of low minute volumes with fentanyl and sufentanil, but soon after epidural injection, i.e., at the time that analgesia was produced. None of the epidurally injected opiates had a significant delayed effect on respiration. However, one of the seven rats treated epidurally with the higher dose of morphine developed depression of the minute volume response to 8% CO2 in air as late as 7 hours after the injection. We conclude that epidural injection, in contrast to subcutaneous injection, of analgesic doses of morphine, meperidine, fentanyl, and sufentanil produces no significant respiratory effects.