Antagonism Of Morphine Analgesia Research Articles

Reduction of prefrontal purinergic signaling is necessary for the analgesic effect of morphine

SummaryMorphine is commonly used to relieve moderate to severe pain, but repeated doses cause opioid tolerance. Here, we used ATP sensor and fiber photometry to detect prefrontal ATP level. It showed that prefrontal ATP level decreased after morphine injection and the event amplitude tended to decrease with continuous morphine exposure. Morphine had little effect on prefrontal ATP due to its tolerance. Therefore, we hypothesized that the analgesic effect of morphine might be related to ATP in the medial prefrontal cortex (mPFC). Moreover, local infusion of ATP partially antagonized morphine analgesia. Then we found that inhibiting P2X7R in the mPFC mimicked morphine analgesia. In morphine-tolerant mice, pretreatment with P2X4R or P2X7R antagonists in the mPFC enhanced analgesic effect. Our findings suggest that reduction of prefrontal purinergic signaling is necessary for the morphine analgesia, which help elucidate the mechanism of morphine analgesia and may lead to the development of new clinical treatments for neuropathic pain.

Dezocine Antagonizes Morphine Analgesia upon Simultaneous Administration in Rodent Models of Acute Nociception

Background: Dezocine is a powerful analgesic that can be less addictive than morphine, yet how the two drugs interact in vivo is poorly understood. Here we administered dezocine alone or in combination with morphine to different acute nociception paradigms to explore the interactions of the 2 drugs upon co-administration. Objective: To evaluate how dezocine interacts with morphine in different acute nociception paradigms. Study Design: Laboratory animal study. Setting: Zhejiang University School of Medicine, Hangzhou, China. Methods: Healthy mice were treated with saline, dezocine (0.625 – 2.5 µg), or a combination of dezocine with morphine (2.5 µg). Tail withdrawal latency (TWL) was analyzed prior to and 30 minutes after drug administration. Rats were treated with saline, morphine (3 mg/kg), dezocine (3 mg/kg), or a combination of both drugs. The animals were then left uninjured, subjected to plantar incision, or underwent formaldehyde-induced acute inflammation. Nociception was then analyzed in terms of mechanical threshold (MT) to von Frey stimulation and paw withdrawal latency (PWL) to thermal stimulation. Formaldehyde-induced pain score was calculated based on the duration of biting and elevating of the animal’s legs. Phosphorylation of extracellular signal-regulated kinase (pERK) was also measured after plantar incision as a molecular index of nociception. Results: Dezocine enhanced TWL but inhibited morphine analgesia in a dose-dependent fashion in mice. Usage of morphine or dezocine alone in uninjured rats increased MT, but co-administering both drugs did not further increase MT. Usage of one drug alone, and both drugs together increased MT and PWL relative to saline at 30 minutes after incision. Usage of one drug alone, but not both drugs together, increased MT and PWL at 120 minutes after incision. Dezocine reduced formaldehyde-induced nociception but co-administering both drugs did not further reduce pain behavior. Limitations: The results were obtained from animal study; clinical investigations will be needed to clarify their interaction. Conclusion: Dezocine antagonizes morphine analgesia on acute nociception upon simultaneous administration. Key words: Dezocine, morphine, acute nociception, analgesia

μ-Opioid Receptor Up-Regulation and Functional Supersensitivity Are Independent of Antagonist Efficacy

Chronic opioid antagonist treatment up-regulates opioid receptors and produces functional supersensitivity. Although opioid antagonists vary from neutral to inverse, the role of antagonist efficacy in mediating the chronic effects of opioid antagonists is not known. In this study, the effects of two putative inverse agonists (naltrexone, naloxone) and a putative neutral antagonist (6beta-naltrexol) were examined. Initially, peak effect (40 min, naltrexone and naloxone; 70 min, 6beta-naltrexol) and relative potency to antagonize morphine analgesia were determined (relative potencies = 1, 2, and 16, 6beta-naltrexol, naloxone, and naltrexone, respectively). Next, mice were infused for 7 days with naloxone (0.1-10 mg/kg/day), naltrexone (10 or 15 mg s.c. pellet), or 6beta-naltrexol (0.2-20 mg/kg/day), and spinal micro-opioid receptor density was examined, or morphine analgesia dose-response studies were conducted. All antagonists up-regulated mu-opioid receptors (60-122%) and induced supersensitivity (1.8-2.0-fold increase in morphine potency). There were no differences in antagonist potency to produce up-regulation or supersensitivity. These data suggest that opioid antagonist-induced mu-opioid receptor up-regulation and supersensitivity require occupancy of the receptor and that antagonist efficacy is not critical. Finally, the ED(50) to precipitate withdrawal jumping was examined in morphine-dependent mice. Naltrexone, naloxone, and 6beta-naltrexol produced withdrawal jumping, although potencies relative to 6beta-naltrexol were 211, 96, and 1, respectively. Thus, antagonist potency to precipitate opioid withdrawal was related to inverse agonist efficacy. Overall, the estimated relative potency of the opioid antagonists was a function of the outcome measured, and inverse agonist activity was not required for mu-opioid receptor up-regulation and supersensitivity.

The preclinical development of Medisorb® Naltrexone, a once a month long-acting injection, for the treatment of alcohol dependence

Oral naltrexone, a nonselective opioid antagonist, is approved for the treatment of alcohol and opioid dependence. However, the efficacy of oral naltrexone is limited by poor patient compliance. To overcome this limitation, attempts have been made to develop an injectable extended-release formulation of naltrexone, including encapsulation into biodegradable polymer microspheres (e.g. Medisorb Naltrexone, Vivitrex (naltrexone long acting injection)). In 1980, NIDA established development goals that they considered optimal for an extended-release formulation. At Alkermes, different formulations were tested with in vitro assays and in vivo models to select a lead formulation. Pharmacokinetic studies in rats confirmed that the principle formulation produced stable, pharmacologically relevant plasma levels of naltrexone for approximately one month following a single injection. The pharmacodynamic effects (antagonism of morphine analgesia) of extended-release naltrexone corresponded well with the pharmacokinetic profile from the same animals. While brain mu-opioid receptor density was found to increase over time in these rats, it did not appear to affect the ability of naltrexone to suppress morphine analgesia. Finally the pharmacokinetic profile of extended-release naltrexone in monkeys confirmed long duration of elevated plasma concentrations of naltrexone. Both naltrexone and the PLG polymer matrix in which it is encapsulated are well tolerated. Clinical trials of Vivitrex are currently ongoing in alcohol dependent patients.

Nocistatin potentiates electroacupuncture antinociceptive effects and reverses chronic tolerance to electroacupuncture in mice

Nocistatin (NST) and nociception/orphanin FQ (OFQ) are peptides derived from the same precursor that play opposing roles in pain modulation. OFQ antagonizes morphine analgesia and electroacupuncture (EA)-induced antinociceptive effect. The present study investigates whether NST potentiates EA-induced antinociceptive effect and reverses chronic tolerance to EA in mice. Injection of NST (0.5, 5.0 and 50.0 ng) intracerebroventricularly had no effect on basal thermal latency, but produced a dose-dependent potentiation of EA-induced antinociceptive effect in mice with the maximum response at 5.0 ng. NST (5.0 ng) partly reversed chronic tolerance to EA. These results suggest that NST in the brain might play roles in EA-induced antinociceptive effect and the development of chronic tolerance to EA in mice.

Changes in brain content of nociceptin/orphanin FQ and endomorphin 2 in a rat model of neuropathic pain

Orphanin FQ (OFQ) and endomorphins (EM) are newly characterized members of opioid peptide family. OFQ has been shown to antagonize morphine analgesia at supraspinal level, whereas endomorphins are highly selective endogenous ligands for mu receptor, showing analgesic effect at both spinal and supraspinal level. OFQ and EM-2 (EM2) immunoreactivity (ir) was measured by radioimmunoassay in nociception-related brain areas of rats subjected to L5/L6 spinal nerve ligation, using sham operated rats as control. It was found that: (1) the content of EM2-ir of spinal nerve ligated rats showed a significant increase (778%) in periaqueductal gray (PAG), and a significant decrease (43%) in striatum, compared with the control group. (2) a significant increase of the content of OFQ-ir was found in amygdala (+841%) and PAG (+459%), respectively in spinal nerve ligated rats. High pressure liquid chromatography showed that the EM2-ir and OFQ-ir were both heterogeneous with the major part eluting at the position of EM2 and OFQ standard, respectively. These results suggest that spinal nerve ligation induces significant changes in the content of EM2-ir and OFQ-ir in some discrete brain areas, which may play a role in nociceptive modulation.

Nocistatin, a peptide reversing acute and chronic morphine tolerance.

It has been reported that intracerebroventricular (i.c.v.) injection of nociception/orphanin FQ (OFQ) can antagonize morphine analgesia, whereas i.c.v. OFQ antibody can reverse morphine tolerance. Nocistatin (NST) is a recently characterized neuropeptide possessing an antagonizing effect on OFQ. Here we examine whether i.c.v. NST would result in a reversal of morphine tolerance. The results showed that: (1) i.c.v. NST at doses of 0.005, 0.05, 0.5, 5 or 50 ng per rat produced a bell-shaped dose-dependent reversal of chronic morphine tolerance, with maximum response at 0.5 ng. (2) Acute morphine tolerance could also be reversed, albeit partially, by i.c.v. NST at 0.5 ng. (3) The reversal of acute and chronic morphine tolerance by NST was completely abolished when NST (0.5 ng) was co-injected with (8 microg) OFQ. Since OFQ and NST are derived from the same preprohormone, the profile of its splicing in the CNS may play an important role in determining the effectiveness of morphine analgesia.

Antianalgesic Action of Dynorphin A Mediated by Spinal Cholecystokinin

Previous work indicates that the antianalgesic action of pentobarbital and neurotensin administered intracerebroventricularly in mice arises from activation of a descending system to release cholecystokinin (CCK) in the spinal cord where CCK is known to antagonize morphine analgesia. Spinal dynorphin, like CCK, has an antianalgesic action against intrathecally administered morphine. This dynorphin action is indirect; even though it is initiated in the spinal cord, it requires the involvement of an ascending pathway to the brain and a descending pathway to the spinal cord where an antianalgesic mediator works. The aim of the present investigation was to determine if the antianalgesic action of intrathecal dynorphin A involved spinal CCK. All drugs were administered intrathecally to mice in the tall flick test. Morphine analgesia was inhibited by dynorphin as shown by a rightward shift of the morphine dose-response curve. The effect of dynorphin was eliminated by administration of the CCK receptor antagonists lorglumide and PD135 158. One hour pretreatment with CCK antiserum also eliminated the action of dynorphin. On the other hand, the antianalgesic action of CCK was not affected by dynorphin antiserum. Thus, CCK did not release dynorphin. Both CCK and dynorphin were antianalgesic against DSLET but not DPDPE, δ2 and δ1 opioid receptor peptide agonists, respectively. The results suggest that the antianalgesic action of dynorphin occurred through an indirect mechanism ultimately dependent on the action of spinal CCK.

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.

Supraspinal Flumazenil Inhibits the Antianalgesic Action of Spinal Dynorphin A [1–17

DynorphinA (Dyn) administered intrathecally or released spinally in mice produces antianalgesia, that is, antagonizes morphine analgesia (tail-flick test). Spinal transection eliminates this Dyn antianalgesia. Present results in mice show that intracerebroventricular administration of flumazenil, a benzodiazepine receptor antagonist, also eliminated the antianalgesic action of Dyn; flumazenil in the brain eliminated the suppressant effect of intrathecal Dyn on intrathecal and intracerebroventricular morphine-induced antinociception. Intracerebroventricular clonidine, naloxone, and norbinaltorphimine release spinal Dyn. The latent antinociceptive actions of these compounds were uncovered by intracerebroventricular flumazenil. Thus, Dyn, given intrathecally or released spinally, activates a pathway that is inhibited by intracerebroventricular flumazenil. Dyn antianalgesia is not significantly altered by intracerebroventricular administration of bicuculline and picrotoxin, suggesting that activation of the gamma-aminobutyric acid receptor has little if any involvement in the antianalgesic action of Dyn. The antagonistic effect of Dyn seems to be mimicked by benzodiazepine agonists. Furthermore, administration of a benzodiazepine receptor inverse agonist (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) inhibited Dyn antianalgesia as did flumazenil. Thus, flumazenil, through a benzodiazepine antagonist or inverse agonist action, interrupts, as does spinal transection, the neuronal circuit (cord/brain/cord) necessary for the antianalgesic action of spinal Dyn. Because Dyn antianalgesia is an indirect action, activation of the neuronal circuit must lead to the release of a direct-acting antianalgesic mediator in the spinal cord.

Morphine analgesia in the formalin test: reversal by microinjection of quaternary naloxone into the posterior hypothalamic area or periaqueductal gray

Bilateral microinjection of 5 nmol morphine into the posterior hypothalamic area (PHA), periaqueductal gray matter (PAG) or ventral tegmental area (VTA) elicits powerful suppression of nociceptive behaviors in the formalin test, an animal model of injury produced pain. The object of the present study was to determine whether analgesia in the formalin test (50 μl 2.5% formalin injected s.c. in one hindpaw) induced by systemically administered morphine requires opioid action at these sites, or other putative sites of opioid action. Morphine sulphate (6 mg/kg s.c.) produced almost complete analgesia in the second phase of the formalin test (30–50 min after formalin). Bilateral microinjection of the quaternary opioid antagonist naloxone methobromide (NxBr, 28 ng in 0.5 μl, 22 min after morphine) into the PHA completely abolished morphine analgesia, while NxBr into PAG partially reversed analgesia. Microinjection of NxBr into the VTA, central nucleus of the amygdala, habenula, striatum, nucleus accumbens or hypothalamic sites outside the PHA did not antagonize morphine analgesia, although microinjections into some of these sites appeared to reduce the cataleptogenic effects of morphine. The data indicate that the PHA and PAG are probably the primary sites of action of morphine in the formalin test.

Orphanin FQ potentiates formalin-induced pain behavior and antagonizes morphine analgesia in rats

The present study was designed to observe the effect of orphanin FQ (OFQ, also known as `nociceptin'), a newly-discovered neuropeptide, on pain behavior and morphine analgesia evaluated by formalin test in rats. It was found that intracerebroventricular (i.c.v.) injection of 0.1 μg OFQ had no effect on formalin-induced pain behavior; but 1, 5, 10 or 20 μg OFQ produced prolonged lifting, licking, biting or shaking of the affected paw with higher pain scoring in dose dependent manner. Repeated i.c.v. injection of antisense olignucleotide (ASO) complementary to OFQ receptor but not mismatch olignucleotide (MSO) resulted in the decrease of pain behavior; in such circumstances, OFQ showed no enhancing effect on formalin nociception. OFQ (0.1 or 1 μg, i.c.v.) significantly attenuated morphine analgesia and ASO could validly antagonize the effect of it. Pretreatment with MSO had no such effect. The present results suggest that OFQ enhances the pain behavior of rat and antagonizes morphine analgesia in formalin test.

Cellular mechanism for anti-analgesic action of agonists of the kappa-opioid receptor.

The analgesic effect of clinically used exogenous opioids, such as morphine, is mediated primarily through mu-opioid receptors, but the function of the kappa-receptor in opioid analgesia is unclear. Although kappa-receptor agonists can produce analgesia, behavioural studies indicate that kappa agonists applied intravenously or locally into the spinal cord antagonize morphine analgesia. As morphine, a primary mu agonist, also binds to kappa-receptors and the analgesic effectiveness of morphine decreases with repeated use (tolerance), it is important to understand the mechanism for the functional interaction between kappa- and mu-opioid receptors in the central nervous system. Here we present in vitro electrophysiological and in vivo behavioural evidence that activation of the kappa-receptor specifically antagonizes mu-receptor-mediated analgesia. We show that in slice preparations of a rat brainstem nucleus, which is critical for the action of opioids in controlling pain, functional kappa- and mu-receptors are each localized on physiologically different types of neuron. Activation of the kappa-receptor hyperpolarizes neurons that are activated indirectly by the mu-receptor. In rats, kappa-receptor activation in this brainstem nucleus significantly attenuates local mu-receptor-mediated analgesia. Our findings suggest a new cellular mechanism for the potentially ubiquitous opposing interaction between mu- and kappa-opioid receptors and may help in the design of treatments for pain.

Pharmacological characterization of buprenorphine, a mixed agonist–antagonist with κ3 analgesia

Buprenorphine is a mixed opioid agonist/antagonist analgesic. This study was designed to determine the role of opioid receptor subtypes, especially κ 3, in buprenorphine-induced analgesia in mice. Buprenorphine, when injected systemically, revealed a potent analgesic effect by tailflick assay, with a biphasic dose–response curve, which was reversed by naloxone. The presence of analgesic cross-tolerance between buprenorphine and naloxone benzoylhydrazone (NalBzoH) and morphine indicated a role for κ 3 and μ receptor subtype in buprenorphine analgesia. Additional studies with selective opioid antagonists indicated κ 1 mechanisms of action. We did not detect any involvement of the δ receptor subtype. Low doses of buprenorphine antagonized morphine analgesia, while high doses of buprenorphine coadministered with morphine elicited increasing analgesia in a dose-dependent manner. These findings suggest that buprenorphine elicits analgesia through an interaction with κ 3 receptors and to a lesser extent with κ 1 as well as its activity as partial μ receptor agonist.

Pharmacological characterization of KT-90 using cloned μ-, δ- and κ-opioid receptors

We analyzed the pharmacological characteristics of (−)-3-acetyl-6β-acetylthio- N-cyclopropylmethyl-normorphine (KT-90) using Chinese hamster ovary (CHO) cells expressing cloned rat μ-, δ- and κ-opioid receptors. KT-90 displaced the specific binding of the following radiolabeled ligands selective to the μ-, δ- and κ-opioid receptors, [ 3H][ d-Ala 2,MePhe 4,Gly(ol) 5]enkephalin (DAMGO), [ 3H][ d-Pen 2, d-Pen 5]enkephalin (DPDPE), [ 3H] (+)-(5α,7α,8β)- N-methyl- N-[7-(1-pyrrolidinyl)-1-oxaspiro-4,5)dec-8-yl]benzeneacetamide (U69,593), with K i values of 3.3 ± 0.7, 22.8 ± 1.5 and 1.9 ± 0.3 nM, respectively. In CHO cells expressing the μ-, δ- and κ-opioid receptors, KT-90 inhibited forskolin (10 μM)-induced cyclic AMP accumulation in a concentration-dependent manner with IC 50 values of 2337 ± 750, 17.3 ± 4.6 and 2.0 ± 0.1 nM, respectively. The maximal inhibitory effects of KT-90 in the cells expressing μ-, δ- and κ-opioid receptors were significantly lower than those of the type-selective agonists DAMGO, DPDPE and U69,593, respectively. These results indicated that KT-90 acts as a partial agonist on μ-, δ and κ-opioid receptors. KT-90 (10 and 100 nM), when added with morphine, produced a rightward shift of the concentration-response curve of morphine to inhibit the cyclic AMP accumulation in CHO cells expressing μ-, but not δ- or κ-, opioid receptors. This finding is consistent with the findings that lower doses of KT-90 antagonize morphine analgesia in vivo.

Cholecystokinin octapeptide (CCK-8) antagonizes morphine analgesia in nucleus accumbens of the rat via the CCK-B receptor

The analgesic effect of systemic morphine (4 mg/kg, s.c.) was antagonized in a dose-dependent manner by cholecystokinin octapeptide (CCK-8) (0.1–0.5 ng) administered bilaterally to the nucleus accumbens of the rat. This effect of CCK-8 could be reversed by devazepide, a CCK-A receptor antagonist, at 50 ng and 200 ng and by L-365,260, a CCK-B receptor antagonist, at 5 ng administered bilaterally to the nucleus accumbens. A marked potentiation of morphine analgesia was achieved by anti-opioid effect of CCK-8 in the nucleus accumbens is 40 times more potent than devazepide it is suggested that the intra-nucleus accumbens injection of 200 ng devazepide or 5 ng L-365,260. Since the effect of L-365,260 in antagonizing the anti-opioid effect of CCK-8 is mediated by CCK-B receptors. In conclusion, nucleus accumbens is a strategic site where CCK-8 exerts an anti-opioid activity, most probably via the CCK-B receptors.

Functional antagonism of morphine analgesia by (+)-pentazocine: evidence for an anti-opioid σ1 system

Both (+)-pentazocine and (−)-pentazocine antagonize morphine analgesia equally well. This lack of stereospecificity implies an non-opioid mechanism of action. The antagonism of morphine analgesia by (+)-pentazocine is reversed by haloperidol, a potent dopamine D 2 and σ receptor antagonist. The inactivity of the highly selective dopamine D 2 receptor antagonist (−)-sulpiride indicates that both (+)-pentazocine and haloperidol are acting through σ receptors. Haloperidol, but not (−)-sulpiride, also enhances morphine analgesia. Together, these results suggest the presence of a tonically active anti-opioid σ system within the brain.

Potentiation of Electroacupuncture-Induced Analgesia by Cck-B Antagonist L-365, 260 in Wistar Rats but Not in Acoustically-Evoked Epileptic Rats

Cholecystokinin octapeptide (CCK-8) is a neuropeptide with potent anti-opioid activity, which can antagonize morphine analgesia at nanogram dosage through activation of the CCK-B receptor in the central nervous system (CNS) of the rat. In the present study the CCK-B antagonist L-365,260 was injected intracerebroventricularly (icv) to Wistar rats to see its effect on the analgesia induced by electroacupuncture (EA) stimulation. A marked potentiation of EA-induced analgesia was observed. This potentiation was more prominent when EA of higher frequency was used, showing a rank order of 100Hz &gt; 15Hz = 2/15Hz ≫ 2Hz. In a strain of rat with acoustically-evoked epileptic seizures (P77PMC rats), an extraordinarily strong analgesic effect was observed when EA of 100Hz was used; an effect similar to that in Wistar rats pre-treated with L-365,260. However, icv injected L-365,260 did not potentiate the analgesic effect induced by EA of any frequency in P77PMC rats. The results suggest that high frequency EA is more likely to increase the release of CCK-8 in the CNS as compared to low frequency EA; and also that P77PMC rats may have a functional deficit of the central CCK system probably due to a reduced rate of release of CCK-8 in the CNS, following EA stimulation.

Dynorphin blocks opioid inhibition of macrophage-colony stimulating factor-induced proliferation of bone marrow cells

We previously reported that morphine inhibits macrophage-colony stimulating factor (M-CSF)-induced proliferation of mouse bone marrow cells, both in vivo and in vitro, in a dose-dependent manner. We now report that either dynorphin A-(1–13) or dynorphin A-(1–10) amide, though having no effect on proliferation by themselves at concentrations less than 0.1 mM, can block the inhibitory effect of morphine both in vivo and in vitro, in a dose-dependent manner. The opioid antagonist naloxone can also block morphine's inhibitory effect on bone marrow cell proliferation in vivo, but has no effect in vitro. Dynorphin A-(1–13) was also able to block the dramatic reduction of spleen weight observed in animals chronically treated with morphine. Thus dynorphin, which has previously been shown to antagonize morphine analgesia, is also able to antagonize some of the immunosuppressive effects of morphine.

Antinarcotic Effects of Standardized Ginseng Extract G115 on Morphine

The study was undertaken to determine the antagonism of morphine analgesia by the standardized ginseng extract G115 from Panax ginseng, the inhibitory effects of orally administered G115 on the development of morphine-induced tolerance and physical dependence, the hepatic glutathione levels, the inhibitory effects of intraperitoneally administered G115 on the dopamine receptor supersensitivity, and the reverse tolerance to the locomotor accelerating effect of morphine. G115 significantly inhibits the development of morphine-induced tolerance and physical dependence, the hepatic glutathione level decrease induced by morphine multiple injections, the development of morphine-induced dopamine receptor supersensitivity, and reverse tolerance to the locomotor accelerating effect of morphine. It did not, however, antagonize morphine analgesia.