Potentiation Of Morphine Analgesia Research Articles

Potentiation of morphine analgesia by BQ123, an endothelin antagonist

Several neurotransmitter mechanisms have been proposed to play a role in the actions of morphine. The present study is the first to provide evidence that central endothelin (ET) mechanisms are involved in the modulation of pharmacological actions of morphine. The effect of intracerebroventricular (i.c.v.) administration of endothelin-A (ET A) antagonist, BQ123, on morphine-induced analgesia, hyperthermia, and catalepsy was determined in the rat. Morphine produced a significant increase in tail-flick latency as compared to control group. Pretreatment with BQ123 significantly potentiated the effect and duration of morphine (2 and 8 mg/kg, s.c.)-induced analgesia as compared to vehicle-pretreated control rats. The hyperthermic effect of morphine was not only significantly greater in BQ123-pretreated rats but also lasted for more than 6 h. ET antagonist, BQ123, did not affect the pharmacological effect of morphine on cataleptic behavior. These studies demonstrate that BQ123, a specific ET A receptor antagonist, significantly potentiated morphine-induced analgesia and hyperthermia in rats without affecting morphine-induced cataleptic behavior. [ 3 H ]-Naloxone binding was carried out to determine the possibility of BQ123 acting on opiate receptors. It was found that morphine could displace [ 3 H ]-naloxone but BQ123 did not affect [ 3 H ]-naloxone binding even at 1000 nM concentration. Therefore, it can be concluded that BQ123 does not act on opioid receptors. This is the first report suggesting that an ET A antagonist, BQ123, significantly potentiates the analgesic effect of morphine, possibly through a nonopioid mechanism.

Dissociation of pharmacological pro- and anti-opioid effects by neuropeptide FF analogs

Neuropeptide FF (NPFF) and its analog 1DMe ([D-Tyr1,(NMe)Phe3]NPFF) have been shown to reverse or potentiate morphine analgesia in rat depending on the supraspinal or spinal site of injection. The properties, in the mouse tail-flick test, of 1DMe and its related compound Nic-1DMe (Nicotinoyl-Pro-1DMe) were investigated after their local (i.c.v. and i.t.) and systemic administration. Whereas Nic-1DMe and 1DMe exhibit the same affinity and selectivity towards NPFF1 and NPFF2 receptors, Nic-1DMe, in contrast to 1DMe, is unable to inhibit morphine-induced analgesia after i.c.v. and i.p. administration. Conversely, after i.t. and i.p. administration, both neuropeptide FF analogs could potentiate morphine analgesia. Differences in disposition parameters between 1DMe and Nic-1DMe are evidenced, suggesting that the two neuropeptide FF analogs could stimulate differentially supraspinal neuropeptide FF receptors. The predominant activation of spinal neuronal pathways by Nic-1DMe could explain the selective pro-opioid action of this compound after i.t., i.c.v. and i.p. administration.

Effect of chronic morphine treatment on the biosynthesis of agmatine in rat brain and other tissues

Agmatine is an endogenous amine derived from the decarboxylation of arginine by arginine decarboxylase (ADC), and metabolized to putrescine by agmatinase. Exogenously administered agmatine has several biological actions including its ability to potentiate morphine analgesia and block symptoms of morphine tolerance/withdrawal in rats. To investigate the role of endogenous agmatine in this action, we sought to determine whether chronic exposure to morphine and induction of withdrawal modulate the synthesis of agmatine in rat brain and other tissues. Exposure of rats to morphine for three days significantly decreases the activity of ADC and the levels of agmatine in rat liver, kidney, brain, aorta and intestine with no changes in agmatinase activity. The precipitation of withdrawal syndrome by injecting naloxone further decreases ADC activity and agmatine levels in these tissues. We conclude that endogenous agmatine may play an important role in regulating morphine tolerance/dependence and withdrawal symptoms.

Effects of diltiazem and MK-801 on morphine analgesia and pharmacokinetics in mice

The effects of diltiazem, an L-type calcium channel blocker, and MK-801, a non-competitive N-methyl- d-aspartate (NMDA) receptor antagonist on morphine analgesia and pharmacokinetics were examined in mice. Mice received a subcutaneous injection of morphine (3.2 mg/kg) 30 min after a subcutaneous injection of diltiazem or MK-801. Diltiazem (20–60 mg/kg) potentiated morphine analgesia and increased serum morphine levels in a dose-dependent manner. MK-801 (0.3 mg/kg) significantly attenuated morphine analgesia but had no significant effect on serum or brain morphine levels. These results suggest that a modification of morphine metabolism is involved, at least in part, in the ability of diltiazem to enhance morphine analgesia, whereas MK-801 attenuates morphine analgesia without affecting morphine pharmacokinetics.

The nociceptin/orphanin FQ receptor antagonist, [Nphe1]NC(1-13)NH2, potentiates morphine analgesia.

Nociceptin/orphanin FQ (NC) and its receptor (OP4) represent a novel peptide/receptor system which has been implicated in the regulation of various central functions, including pain. The aim of the present study was to explore the involvement of the endogenous NC/OP4 system in the modulation of opioid analgesia using the selective OP4 receptor antagonist [Nphe1]NC(1-13)NH2. Experiments were performed in mice exposed to acute as well as chronic treatment with morphine. [Nphe1]NC(1-13)NH2, injected i.c.v. at 30 nmol, strongly potentiated the analgesic effect of supraspinal morphine (1 nmol, i.c.v.) while it only slightly increased the antinociceptive activity of morphine given systemically (5 mg/kg, s.c.). [Nphe1]NC(1-13)NH, (30 nmol, i.c.v.) also potentiated morphine analgesia in mice made tolerant to the opiate (30 mg/kg/day for 4 days). These findings implicate the endogenous NC signaling as a modulator of morphine analgesia and tolerance.

Magnesium sulfate potentiates morphine antinociception at the spinal level.

Intrathecal magnesium sulfate coinfusion with morphine increases antinociception in normal rats; however, because magnesium also delays the onset of tolerance, it is not clear whether this additional antinociception is a result of potentiated analgesia or tolerance abatement. We examined the antinociceptive interaction of intrathecal (IT) bolus magnesium sulfate and morphine in morphine naive rats and those with mechanical allodynia after a surgical incision. After intrathecal catheter implantation, rats were given preinjections of magnesium or saline, followed by injections of morphine or saline. In morphine naïve rats, IT bolus magnesium sulfate 281 and 375 microg followed by IT morphine 0.25 or 0.5 nmol enhanced peak antinociception and area under the response versus time curve two-to-three-fold in the tail-flick test as compared with morphine alone. Likewise, in rats with incisional pain, IT bolus magnesium sulfate 188 and 375 microg followed by morphine 0.5 nmol reduced mechanical allodynia, whereas morphine 0.5 nmol alone did not. This study suggests that IT magnesium sulfate potentiates morphine at a spinal site of action. Magnesium sulfate potentiates morphine analgesia when coadministered intrathecally in normal rats, and in an animal model of mechanical allodynia after a surgical incision. These results suggest that intrathecal administration of magnesium sulfate may be a useful adjunct to spinal morphine analgesia.

Abuse Potential of Morphine/Dextromethorphan Combinations

The potentiation of morphine analgesia by dextromethorphan raises the issue of whether dextromethorphan also potentiates those actions of morphine that lead to abuse. Clinical pharmacology experiments indicated that dextromethorphan does not potentiate the euphorigenic and miotic actions of morphine. Morphine suppresses the dysphoric action of dextromethorphan. A second set of experiments indicated that dextromethorphan does not alter the response to naloxone-precipitated withdrawal. In a third set of experiments, dextromethorphan did not alter the morphine-induced depression in the slope of the increase in minute volume in response to breathing increased CO 2. In contrast to potentiation of analgesia, dextromethorphan does not enhance the euphorigenic, physical dependence, and respiratory depressant actions of morphine. These findings indicate that dextromethorphan does not enhance the abuse potential of morphine and that the potentiation of analgesia appeared to be selective.

Inescapable shock-induced potentiation of morphine analgesia in rats: Sites of action.

Inescapable shock-induced potentiation of morphine analgesia in rats: Sites of action.

Inescapable shock-induced potentiation of morphine analgesia in rats: sites of action.

Inescapable shock (IS) enhances analgesia to systemic morphine (MOR) 24 hr later. IS activates serotonin neurons in the dorsal raphe nucleus (DRN), rendering them hyperexcitable. These studies tested whether IS potentiates the analgesic effect of MOR microinjected in the DRN, as predicted by this hypothesis. To test site specificity, the effect of previous IS was examined on MOR microinjected lateral to the DRN and into 2 other sites that support MOR analgesia, the nucleus raphe magnus (NRM) and spinal cord. Twenty-four hours after IS, potentiated analgesia was observed after 0.5 microg MOR microinjected into, but not lateral to, the DRN. Potentiated analgesia was also observed after NRM (1.0 microg) and spinal cord (3.0 microg) MOR microinjections. These data suggest that IS-induced excitability changes within the DRN synergize with opiates microinjected in other analgesia areas and that this potentiates the responses to opiates 24 hr after IS.

Psychostimulant Drugs Potentiate Morphine Analgesia in the Formalin Test

Recent research has shown that the psychostimulant drug dextroamphetamine can increase the analgesia produced by opioids. Despite the strong, positive results in human clinical subjects and in animals, this combination is rarely used in clinical practice. The purpose of this paper is to investigate whether the psychostimulant drug methylphenidate (MP) can potentiate morphine analgesia in the rat formalin test, and to compare its effectiveness to that of dextroamphetamine (AMP). The formalin test was used because its long-lasting pain of moderate intensity resembles human clinical pain. Two different drug administration times were used to observe whether the early phase of the formalin response would be differentially affected by the drugs. At Drug Administration Time 1, rats received morphine 30 min prior to the formalin injection (−30 min) and MP or AMP 20 min prior to the formalin injection (−20 min). At Drug Administration Time 2, rats received morphine 10 min prior to the formalin injection (−10 min) and MP or AMP immediately prior to the formalin injection (0 min). All drugs were given subcutaneously. The results indicate that low doses of MP or AMP potentiate the analgesic effects of morphine. The clinical value of these drug combinations merits further investigation in animals and in humans.

Further evidence that nitric oxide modifies acute and chronic morphine actions in mice

The effects of the nitric oxide (NO) synthase inhibitor, N ω-nitro- l-arginine ( l-NNA, 2.5–10 μg i.c.v.), and the NO synthesis precursor, l-arginine ( l-Arg, 2.5–10 μg i.c.v.), on morphine-induced analgesia, and on morphine-induced tolerance and dependence were examined in mice. Administration of l-NNA diminished the morphine-induced analgesia. l-Arg pretreatment increased the analgesic effect of morphine. Repeated pretreatment (three times, at 24-h intervals) with l-NNA diminished both acute and chronic tolerance to morphine, whereas both the acute and the chronic morphine-induced tolerance increased after the repeated (three times, at 24-h intervals) administration of l-Arg. Neither l-NNA nor l-Arg affected the signs of morphine dependence, as assessed by naloxone (1 mg/kg, s.c.)-precipitated withdrawal. Our data suggest that increased NO synthesis potentiates morphine analgesia and enhances the development of morphine tolerance in mice.

Endogenous orphanin FQ: evidence for a role in the modulation of electroacupuncture analgesia and the development of tolerance to analgesia produced by morphine and electroacupuncture.

1. Our previous work has demonstrated that exogenously administered orphanin FQ (OFQ) antagonizes morphine analgesia and electroacupuncture analgesia (EAA) in the brain and potentiates morphine analgesia and EAA in the spinal cord of the rat. In the present study we evaluated the role of endogenously released OFQ in the development of tolerance to morphine and electroacupuncture (EA) and the analgesia produced by electroacupuncture, by use of the IgG fraction of an anti-OFQ antibody (OFQ-Ab) microinjected into the rat central nervous system (CNS). 2. EAA was produced by stimulating rats at a frequency of 100 Hz. Rats were classified as either high responders (HR) or low responders (LR) based on the analgesic effects of EA. LRs could be converted into HRs by the intracerebroventricular (i.c.v.) microinjection of OFQ-Ab at both 1:1 and 1:10 dilutions but not 1:100. HRs could be changed into LRs by the intrathecal (i.t.) injection of OFQ-Ab at both 1:1 and 1:10 dilutions, but not 1:100. 3. Acute morphine tolerance was induced in rats by repeated subcutaneous (s.c.) injections of morphine (5 mg kg, every 2 h) for 16 h. When injected i.c.v. the OFQ-Ab (1:1 dilution) had no effect on the development of acute morphine tolerance. 4. Chronic morphine tolerance was produced in rats by repeated injection of morphine (5-60 mg kg, s.c., 3 x a day) for 6 days. I.c.v. injection of OFQ-Ab (1:1 dilution) reversed this type of morphine tolerance in rats by 50% (P < 0.01). 5. Acute tolerance to the analgesia produced by EA developed after 6 h of continuous (100 Hz, 3 mA) stimulation. This tolerance was almost completely reversed by the i.c.v. injection of OFQ-Ab (1:1 dilution) (P < 0.05). 6. Chronic tolerance to the analgesic effect of EA was produced by repeatedly administering increasing current (1, 2 and 3 mA, each lasting for 10 min, for a total of 30 min) at a frequency of 100 Hz once a day for 6 days. I.c.v. injection of OFQ-Ab (1:1 dilution) reversed this kind of tolerance by 50% (P < 0.01). 7. Together these results suggest that 100 Hz EA may enhance the release of endogenous OFQ in the CNS of the rat, which in turn may act to antagonize EA-produced analgesia in the brain but potentiate EA produced analgesia in the spinal cord. Therefore, OFQ appears to play an important role in the development of tolerance to the analgesic effects produced by EA. 8. The mechanisms underlying the development of acute morphine tolerance and chronic morphine tolerance appear to be different. Central OFQ may play an important role in the development of tolerance after chronic morphine administration.

Inescapable shock-induced potentiation of morphine analgesia in rats: Involvement of opioid, GABAergic, and serotonergic mechanisms in the dorsal raphe nucleus.

Inescapable shock-induced potentiation of morphine analgesia in rats: Involvement of opioid, GABAergic, and serotonergic mechanisms in the dorsal raphe nucleus.

14-144 - Potentiation of morphine analgesia and inhibition of dependence development by Ca 2+ channel antagonists

14-144 - Potentiation of morphine analgesia and inhibition of dependence development by Ca 2+ channel antagonists

Inescapable shock-induced potentiation of morphine analgesia.

Exposure to various stressors potentiates nociceptive and nonnociceptive responses to morphine. These phenomena have received little study despite their seeming generality and importance for understanding analgesia and opiate action. The present experiments characterize inescapable shock (IS)-induced potentiation of morphine analgesia. Rats were exposed to IS, equal escapable shocks (ESs), or restraint (control). Potentiation of analgesia (tail-flick [TF] test and hotplate test) was observed only in rats given IS 24 or 48 hr earlier, in agreement with previously reported learned-helplessness effects. Finally, no change in tail temperature or motor function was found that could be inaccurately interpreted as analgesia. The relevance of these findings to stressor-induced enhancement of morphine analgesia and potential substrates of IS effects are discussed.

Inescapable shock-induced potentiation of morphine analgesia in rats: involvement of opioid, GABAergic, and serotonergic mechanisms in the dorsal raphe nucleus.

Exposure of rats to inescapable shock (IS) potentiated the analgesic response to a low dose (1 mg/kg) of morphine 24 hr later. This effect was blocked by naltrexone (10 micrograms), diazepam (5 micrograms), or 8-hydroxy-2-(di-n-propylamine)-tetralin (8-OH-DPAT; 1 microgram) microinjected into the dorsal raphe nucleus (DRN) 15 min before IS. When microinjected into the DRN at the time of tail-flick testing, 8-OH-DPAT also effectively prevented this effect. Further, intra-DRN administration of a beta-carboline mimicked the effects of IS, because rats treated with methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (1 microgram) and simply restrained displayed potentiated morphine analgesia 24 hr later. These data suggest that this phenomenon shares mechanisms in common with other effects of IS at the level of the DRN.

Synthesis and pharmacological evaluation in mice of new non-classical antinociceptive agents, 5-(4-arylpiperazin-1-yl)-4-benzyl-1,2-oxazin-6-ones.

Several 5-(4-arylpiperazin-1-yl)-4-benzyl-1,2-oxazin-6-ones have been synthesized and tested for analgesic activity in a visceral pain model (phenylbenzoquinone-induced writhing test = PBQ test). A good correlation has been found between the antinociceptive effects of drugs and both their lipophilic and steric properties. The most active derivatives 5c and 5f, with intraperitoneal ED50 values of 10.5 and 10.3 mg kg-1 respectively, were more extensively investigated by evaluating their analgesic activity in a somatosensory pain model (hot plate test), as well as their sedative properties. Furthermore, naloxone suppressed the effect of 5c and 5f in the PBQ test, though these derivatives were ineffective to potentiate morphine analgesia. Pretreatment with yohimbine did not significantly attenuate the analgesic effects of 5c and 5f. In addition, pretreatment with 5-hydroxytryptophan associated with carbidopa also failed to potentiate the antinociceptive effects of 5c and 5f. So, a part of the analgesic activity of 5c and 5f seems to be related to an opioidergic mechanisms, especially at the mu receptor level. Molecular modeling studies performed on the opiate drug morphine and on the most stable conformer of 5f showed structural similarities between these two molecules.

The antinociceptive effects of branched-chain amino acids: Evidence for their ability to potentiate morphine analgesia

The effect of branched-chain amino acids (BCAA) on pain threshold was studied in rats. Nociception was induced by the hot-plate analgesia meter, a method measuring supraspinally organized pain responses. After a single intravenous injection of BCAA (320 mg/kg), the percent change in latency time to the pain response significantly increased by 19% in 60 min, and by 22% in 75 min ( p < 0.005), as compared to an injection of an equal volume of a standard concentration of an amino acid solution or physiological saline. Subsequently, we studied the interaction of BCAA with opioid-type analgesia. In combination with intravenously injected morphine (3 mg/kg), BCAA significantly potentiated and prolonged the action of morphine using the hot-plate test. From 5 min after morphine injection, the latencies to a pain response were markedly higher with the combination of BCAA and morphine (+ 80% and + 89% at 5 min after morphine injection, if BCAA was administered 45 or 60 min prior to morphine injection, respectively) when compared with the effect of morphine alone (+ 13% at 5 min; p < 0.005). BCAA demonstrated analgesic effects, which, in combination with morphine, potentiated and prolonged the antinociceptive action of morphine. BCAA may represent a new adjunct treatment modality for acute and chronic pain, and give us further insight into the mechanisms of pain control.

Potentiation of morphine analgesic action in mice by β-carotene

β-Carotene was found to potentiate morphine analgesia in hot plate experiments using mice. Response time was increased by about 100%, and the duration of analgesia was markedly prolonged. These features of β-carotene were a function of the intact molecule, although the closely related compound, α-carotene, also exhibited this property. β-Carotene alone had no effect on the nociceptive response. Other compounds with related structures, metabolic products, or anti-oxidants neither augmented nor antagonized morphine action.

Characterization of the effect of cholecystokinin (CCK) on neurons in the periaqueductal gray of the rat: immunocytochemical and in vivo and in vitro electrophysiological studies

The periaqueductal gray (PAG) is an important integration site for pain, autonomic functions, vocalization, fear and anxiety. Cholecystokinin (CCK) is a major neurotransmitter in the PAG and CCK receptors are heterogeneously distributed within the PAG. Since CCK antagonists are anxiolytic and potentiate morphine analgesia, it is possible that these effects of CCK are mediated through alteration of neuronal activities in the PAG. The goals of this study were to examine the anatomical and physiological properties of the PAG CCK containing systems. The distribution of CCK-containing axons and boutons in PAG was examined using immunohistochemical procedures. These studies show that CCK-like immunoreactive (CCK-LIR) fibers and terminals are present throughout PAG, but are particularly heavily concentrated in a focal column that runs longitudinally throughout the rostrocaudal axis of dorsolateral PAG and in nucleus cuneiformis which represents a caudolateral extension of PAG. The physiological effects of CCK on PAG neurons were examined in both in vivo and in vitro preparations. In the in vivo experiments multibarreled electrodes were used to record from PAG neurons and to apply CCK and the CCK antagonists, CR1409 and proglumide. Of 37 neurons recorded in vivo, CCK caused excitation in 25 cells, inhibited 7 cells and had no effect on 5 cells. The excitatory effect was blocked by CR1409 in 11/11 cells tested. Proglumide blocked the excitatory response of CCK in 12/14 cells. Proglumide blocked the inhibitory effect in 2 of 7 cells, but CR1409 had no effect on CCK-evoked inhibition in 7 cells tested. Extracellular, conventional intracellular and whole cell patch clamping procedures were used to study CCK actions in the in vitro slice preparation. In the extracellular recording experiments, responses of PAG cells to CCK were measured in slices that were maintained at 22°C (room temperature) and at 32°C. CCK excited 40/56, inhibited 7/56 and had no effect on 9/56 cells; excitatory responses were blocked by CR1409 in 32/36 cells and by proglumide in 25/27 cells tested. Inhibitory responses to CCK were unaffected by CR1409, but were blocked in 3/7 cells by proglumide. Conventional intracellular recordings were made from 13 cells. In 11 cells, CCK produced a membrane depolarization that ranged between 5 and 18 mV (mean= 9.0 ± 3.3mV); the firing rates of these cells were increased by as much as 98% (from mean of 1.7 ± 1.0spikes/s to3.3 ± 1.6spikes/s). The effects of CCK on 18 cells were examined in whole cell patch clamp recordings. In 13/18 cells CCK increased the membrane conductance; the reversal potential for CCK had a mean of −51.1 ± 5.7mV. The remaining five neurons did not respond to CCK. From these studies it is concluded that: (1) CCK is a major excitatory transmitter in the PAG; (2) the excitatory effect of CCK is due to membrane depolarization most likely due to increase of Na + and/or Ca 2+ permeability; (3) the excitatory effect of CCK is mediated through postsynaptic mechanisms; and (4) the response to CCK is in part mediated through activation of CCK-A receptors.