First of all, i wanted to put this in another thread as we know that NMDA antagonists definatly work, and i want to keep discussion there selectively of those compounds, and not get the thread cluttered with reports of the things being discussed here not working, or interfering with the NMDA antagonits, they may work perfectly in humans, they may synergize with NMDA antagonists, we dont know yet untill more people try out those compounds. They may also be an alternative for those that cant properly tolerate NMDA antagonists or are unable to get them.
Several compounds worth discussing:
Prenenolone:
All this is very interesting, as this one also is a NMDA positive modulator, and basicly at first sight such as D aspartic acid looks like an agonist.
Its likely that pregnenolone reverses tolerance due to a mechanism distinct from its positive NMDA modulation, i wonder wheter it would interfere with nmda antagonists tough. (i wonder the same about the racetams).
DHEA also reverses benzo and opiate tolerance without acting on NMDA. DHEA and pregnenolone are neurosteroids.
Ultra low dose naltrexone and proglumide are also 2 compounds id like to see discussed here.
D aspartic acid
It appears that someone reported D aspartic acid to reverse ketamine tolerance, besides that he said it worked agains tolerance to other drugs too.
While it appears to act as a glutamate agonist, this experience combined with my own experience adding it to memantine makes me think it somehow downregulate the NMDA receptors, the reason being that in my experience it reversed the memantine adaptation period (the cognitive effects wich imo go away because during the adaptation phase the NMDA receptors partionally upregulate). It would make sense as NMDA downregulation explains ketamine tolerance reversal and also tolerance reversal to all other drugs nmda antagonists are effective for.
For more info about D aspartic acid:
http://www.ergo-log.com/dasparticacidtestosterone.html
Its been discussed on fora like bodybuilding.com because it raises testosterone quite a bit.
(This is only based on one anecdotal report).
Cheers.
Several compounds worth discussing:
Prenenolone:
J Neurochem. 2008 Oct;107(2):510-21. Epub 2008 Aug 14.
Pregnenolone sulfate induces NMDA receptor dependent release of do
pamine from synaptic terminals in the striatum.
Whittaker MT, Gibbs TT, Farb DH.
Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA.
Abstract
Neuromodulators that alter the balance between lower-frequency glutamate-mediated excitatory and higher-frequency GABA-mediated inhibitory synaptic transmission are likely to participate in core mechanisms for CNS function and may contribute to the pathophysiology of neurological disorders such as schizophrenia and Alzheimer's disease. Pregnenolone sulfate (PS) modulates both ionotropic glutamate and GABA(A) receptor mediated synaptic transmission. The enzymes necessary for PS synthesis and degradation are found in brain tissue of several species including human and rat, and up to 5 nM PS has been detected in extracts of postmortem human brain. Here, we ask whether PS could modulate transmitter release from nerve terminals located in the striatum. Superfusion of a preparation of striatal nerve terminals comprised of mixed synaptosomes and synaptoneurosomes with brief-duration (2 min) pulses of 25 nM PS demonstrates that PS increases the release of newly accumulated [3H]dopamine ([3H]DA), but not [14C]glutamate or [3H]GABA, whereas pregnenolone is without effect. PS does not affect dopamine transporter (DAT) mediated uptake of [3H]DA, demonstrating that it specifically affects the transmitter release mechanism. The PS-induced [3H]DA release occurs via an NMDA receptor (NMDAR) dependent mechanism as it is blocked by D-2-amino-5-phosphonovaleric acid. PS modulates DA release with very high potency, significantly increasing [3H]DA release at PS concentrations as low as 25 pM. This first report of a selective direct enhancement of synaptosomal dopamine release by PS at picomolar concentrations via an NMDAR dependent mechanism raises the possibility that dopaminergic axon terminals may be a site of action for this neurosteroid.
J Neurosci. 2003 May 1;23(9):3572-6.
Sigma 1 receptor-related neuroactive steroids modulate cocaine-induced reward.
Romieu P, Martin-Fardon R, Bowen WD, Maurice T.
Centre National de la Recherche Scientifique Unité Mixte de Recherche 5102, University of Montpellier II, 34095 Montpellier cedex 5, France.
Abstract
The sigma1 receptor is critically involved in the rewarding effect of cocaine, as measured using the conditioned place preference (CPP) procedure in mice. Neuroactive steroids exert rapid neuromodulatory effects in the brain by interacting with GABA(A), NMDA, and sigma1 receptors. At the sigma1 receptor level, 3beta-hydroxy-5-androsten-17-one [dehydroepiandrosterone (DHEA)] and 3beta-hydroxy-5-pregnen-20-one (pregnenolone) act as agonists, whereas 4-pregnene-3,20-dione (progesterone) is an efficient antagonist. The present study sought to investigate the action of neuroactive steroids in acquisition of cocaine-induced CPP in C57BL/6 mice. None of these steroids induced CPP alone. However, pretreatment with DHEA or pregnenolone (5-20 mg/kg, s.c.) during conditioning with cocaine (10 mg/kg, i.p.) increased the conditioned score. On the contrary, pretreatment with either progesterone (10 or 20 mg/kg, s.c.) or finasteride (25 mg/kg, twice a day), a 5alpha-reductase inhibitor, blocked acquisition of cocaine (20 mg/kg)-induced CPP. A crossed pharmacology was observed between steroids and sigma1 ligands. The sigma1 antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine blocked cocaine-induced CPP and its potentiation by DHEA or pregnenolone. Progesterone (progesterone is bad) blocked cocaine-induced CPP and its potentiation by the sigma1 agonist igmesine. These results showed that neuroactive steroids play a role in cocaine-induced appetence, through their interaction with the sigma1 receptor. Therefore, neuroendocrine control of cocaine addiction may not involve solely glucocorticoids. The importance of neuroactive steroids as factors of individual vulnerability to drug addiction should, thus, be considered.
PMID: 12736327 [PubMed - indexed for MEDLINE]Free Article
Physiol Res. 2008;57 Suppl 3:S49-57. Epub 2008 May 13.
Neurosteroid modulation of ionotropic glutamate receptors and excitatory synaptic transmission.
Sedlácek M, Korínek M, Petrovic M, Cais O, Adamusová E, Chodounská H, Vyklický L Jr.
Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic.
Abstract
Ionotropic glutamate receptors function can be affected by neurosteroids, both positively and negatively. N-methyl-D-aspartate (NMDA) receptor responses to exogenously applied glutamate are potentiated or inhibited (depending on the receptor subunit composition) by pregnenolone sulphate (PS) and inhibited by pregnanolone sulphate (3alpha5betaS). While PS effect is most pronounced when its application precedes that of glutamate, 3alpha5betaS only binds to receptors already activated. Synaptically activated NMDA receptors are inhibited by 3alpha5betaS, though to a lesser extent than those tonically activated by exogenous glutamate. PS, on the other hand, shows virtually no effect on any of the models of synaptically activated NMDA receptors. The site of neurosteroid action at the receptor molecule has not yet been identified, however, the experiments indicate that there are at least two distinct extracellularly located binding sites for PS mediating its potentiating and inhibitory effects respectively. Experiments with chimeric receptors revealed the importance of the extracellular loop connecting the third and the fourth transmembrane domain of the receptor NR2 subunit for the neurosteroid action. alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors are inhibited by both PS and 3alpha5betaS. These neurosteroids also affect AMPA receptors-mediated synaptic transmission, however, in a rather indirect way, through presynaptically located targets of action.
PMID: 18481915 [PubMed - indexed for MEDLINE]Free Article
Neuropsychopharmacology. 2009 Jul;34(8):1885-903. Epub 2009 Apr 1.
Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia.
Marx CE, Keefe RS, Buchanan RW, Hamer RM, Kilts JD, Bradford DW, Strauss JL, Naylor JC, Payne VM, Lieberman JA, Savitz AJ, Leimone LA, Dunn L, Porcu P, Morrow AL, Shampine LJ.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27705, USA. [email protected]
Abstract
The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents.Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n=9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change=10.38) compared with patients receiving placebo (mean change=2.33), p=0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (r(s)=0.81, p=0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (r(s)=0.74, p=0.046). In addition, baseline pregnenolone(r(s)=-0.76, p=0.037), pregnenolone sulfate (r(s)=-0.83, p=0.015), and allopregnanolone levels (r(s)=-0.83, p=0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (r(s)=0.74, p<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.
PMID: 19339966 [PubMed - indexed for MEDLINE]Free Article
Indian Journal of Pharmacology
Year : 1998 | Volume : 30 | Issue : 1 | Page : 6-15
Potential mechanisms of neurosteroid-induced attenuation of morphine tolerance and dependence
DS Reddy, SK Kulkarni
Objective: The modulatory role of (-aminobutyric acid (GABA)-benzodiazepine-Cl- channel, neuronal Ca 2+ channels, N-methyl-D aspartate (NMDA) and mitochondrial diazepam binding inhibitor receptors in the neurosteroid-induced attenuation of morphine tolerance and dependence was investigated. Methods: Mice were rendered dependent on morphine (10 mgkg, twice daily for 9 days) and the development of tolerance was assessed by tail-flick test. The abstinence behaviour was evaluated by naloxone (2 mg/kg)-induced jumping. Results: Concomitant treatment with neurosteroid pregnenolone sulfate (2 mg/kg), progesterone (5 mg/kg) or 4'-chlordiazepam (0.5 mg/kg) significantly prevented the development of tolerance and also inhibited the naloxone (2 mg/kg)-induced withdrawal jumping in morphine-dependent mice. The effect of 4'-chlordiazepam was blocked by the mitochondrial diazepam binding inhibitor receptor antagonist PK11195 (2 mg/kg), but not by flumazenil (2 mg/kg), a selective benzodiazepine receptor antagonist. In contrast, the effect of progesterone was not affected by PK11195 or flumazenil. As expected, the development of tolerance and dependence observed upon chronic morphine was inhibited by the Ca2+ channel blocker nifedipine or an NMDA receptor antagonist dizocilpine. Further, a combined chronic administration of nifedipine together with neurosteroids pregnenolone sulfate, progesterone or 4'-chlor-diazepam led to an additive inhibitory effects on morphine tolerance or dependence, whereas the dizocilpine effect could not be increased by coadministration of the neurosteroids. Conclusion: The results indicate a role for dihydropyridine-sensitive Ca2+ channels in the action of neurosteroids and mitochondrial diazepam binding receptors in the 4'-chlordiazepm on the development of tolerance and dependence on morphine. Further, the direct involvement of GABAA/benzodiazepine receptor-mediated chloride channel control in the observed neurosteroid effects cannot be unequivocally ruled out.
Eur J Neurosci. 1999 Oct;11(10):3757-60.
The neurosteroid pregnenolone sulphate increases dopamine release and the dopaminergic response to morphine in the rat nucleus accumbens.
Barrot M, Vallée M, Gingras MA, Le Moal M, Mayo W, Piazza PV.
Psychobiologie des Comportements Adaptatifs, INSERM U259, Université Victor Segalen Bordeaux 2, France.
Abstract
Neurosteroids are a subclass of steroids that can be synthesized in the central nervous system independently of peripheral sources. Clinical studies in humans have associated some of these hormones with a generic sensation of 'well-being' and with pathologies such as depression. In rodents, the neurosteroid pregnenolone sulphate (Preg-S) has been shown to present antidepressant-like effects. These observations suggest that neurosteroids could interact with reward-related processes, mood and motivation. However, the possible neural substrates of such an effect remain unclear. In this report, we studied the action of Preg-S on the activity of the mesencephalic dopaminergic projection to the nucleus accumbens which is considered one of the biological substrates of motivation and reward. Both the direct effect of Preg-S and the influence of this hormone on the dopaminergic response to the pharmacological reward provided by the opiate morphine, were studied by means of microdialysis. Pregnenolone sulphate dose-dependently increased dopamine release in the nucleus accumbens. Furthermore, this hormone doubled the dopaminergic response to morphine. These effects were observed for Preg-S doses of 100, 200, and 400 pmol injected intracerebroventricularly. The stimulant effect of Preg-S on dopamine could mediate some of the behavioural effects of neurosteroids and in particular the interaction of these hormones with mood and motivation.
PMID: 10564382 [PubMed - indexed for MEDLINE]
Eur J Pharmacol. 1997 Oct 15;337(1):19-25.
Chronic neurosteroid treatment prevents the development of morphine tolerance and attenuates abstinence behavior in mice.
Reddy DS, Kulkarni SK.
Department of Pharmacology, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Abstract
The effect of neurosteroids on the development of morphine tolerance and dependence was examined in mice. Development of tolerance to the antinociceptive effect of morphine sulfate (10 mg/kg, twice daily for 9 days) was measured in the tail-flick test and dependence was assessed from naloxone (2 mg/kg)-precipitated withdrawal jumps on day 10 of testing. Concomitant chronic administration of neurosteroids, allopregnanolone (0.5 mg/kg), pregnenolone sulfate (2 and 5 mg/kg) or dehydroepiandrosterone sulfate (2 and 5 mg/kg), followed by morphine (10 mg/kg) prevented the development of tolerance to the antinociceptive effect of morphine and suppressed the naloxone-precipitated withdrawal jumps. In contrast, dehydroepiandrosterone acetate (5 mg/kg) failed to modulate the morphine tolerance and dependence. The inhibitory effect was also seen upon concomitant administration of a neurosteroid precursor, progesterone (1-10 mg/kg), and a mitochondrial diazepam binding inhibitor receptor agonist, 4'-chlordiazepam (0.25-1 mg/kg), while an adrenocorticosteroid, hydrocortisone (1 and 10 mg/kg), failed to do so. However, acute treatment with these neurosteroids was not associated with any decrease in withdrawal jumping behavior in morphine-dependent mice. Neurosteroids themselves, at doses employed in the study, did not exert any effects on antinociception. These results support a role for neurosteroids in the development of tolerance to and dependence on morphine and suggest the potential utility of specific neuroactive steroids in its treatment.
PMID: 9389376 [PubMed - indexed for MEDLINE]
Those study's havent been found by me, so i dont deserve any credits for this, many thx for my mate to bring those of preg to my attention.Methods Find Exp Clin Pharmacol. 1997 Jul-Aug;19(6):395-405.
Neurosteroid coadministration prevents development of tolerance and augments recovery from benzodiazepine withdrawal anxiety and hyperactivity in mice.
Reddy DS, Kulkarni SK.
Department of Pharmacology, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Abstract
Neurosteroids are potent and specific modulators of the GABAA receptors which regulate the neuronal activity through diverse neurotransmitter mechanisms. In the present study we investigated the effects of concomitant treatment with various neurosteroids on the development of tolerance and recovery from withdrawal anxiety and hyperactivity to chronic benzodiazepines. Long-term treatment of mice with full allosteric modulator (triazolam 0.25 mg/kg/day for 8 days) or selective allosteric modulator (diazepam 20 mg/kg/day for 21 days) of GABAA receptor induced tolerance to behavioral sedation on actimeter and anxiolytic effects on plus-maze, and produced a marked withdrawal anxiety and hyperactivity syndrome upon abrupt cessation of treatment, respectively. Concomitant progesterone (10 mg/kg, s.c.), a neurosteroid precursor, of 4'-chlordiazepam (0.25 mg/kg, i.p.), a mitochondrial diazepam binding inhibitor (DBI) receptor (MDR) ligand, prevented the development of tolerance and significantly augmented the recovery from withdrawal-induced anxiety and hyperlocomotion to diazepam. When administered alone for 21 days, neither progesterone nor 4'-chlordiazepam produced any per se effects on actimeter or plus-maze when tested on post-withdrawal days. Coadministration of neurosteroid allopregnanolone (AP) (0.25 and 0.5 mg/kg), or pregnenolone sulfate (PS) (2 mg/kg), but not dehydroepiandrosterone sulfate (2 mg/kg), abolished (ABOLISHED - BOOOOOOOOOM!) the development of tolerance and attenuated withdrawal-induced anxiety and hyperlocomotion due to triazolam, without producing any per se behavioral effects when tested at 1 and 2 days after the last injection. Coadministration of flumazenil (5 mg/kg), progesterone (10 mg/kg), 4'-chlordiazepam (0.25 mg/kg), hydrocortisone (100 mg/kg) or nifedipine (2 mg/kg) also prevented the development of tolerance and suppressed the triazolam withdrawal syndrome. However, pretreatment with PK11195 (2 mg/kg), a MDR partial antagonist, reversed the effects of 4'-chlordiazepam on triazolam tolerance and recovery from chronic triazolam. When injected simultaneously, nifedipine, a Ca2+ channel antagonist, potentiated the progesterone- and 4'-chlordiazepam-induced attenuation of triazolam tolerance and withdrawal behavior. These findings suggest that coadministration of neurosteroids allopregnanolone, pregnenolone sulfate and progesterone, and MDR ligand 4'-chlordiazepam prevents the development of tolerance to benzodiazepines and augments the recovery from chronic benzodiazepines. These results indicate that coadministration of neurosteroids may facilitate discontinuation of benzodiazepines in long-term therapy.
All this is very interesting, as this one also is a NMDA positive modulator, and basicly at first sight such as D aspartic acid looks like an agonist.
Its likely that pregnenolone reverses tolerance due to a mechanism distinct from its positive NMDA modulation, i wonder wheter it would interfere with nmda antagonists tough. (i wonder the same about the racetams).
DHEA also reverses benzo and opiate tolerance without acting on NMDA. DHEA and pregnenolone are neurosteroids.
Anesth Analg. 2004 Oct;99(4):1180-4, table of contents.
The effects of intrathecal gabapentin on spinal morphine tolerance in the rat tail-flick and paw pressure tests.
Hansen C, Gilron I, Hong M.
Source
Department of Pharmacology & Toxicology, Kingston General Hospital, Queen's University, Ontario, Canada .
Abstract
Analgesic tolerance to opioids has been described in both experimental and clinical conditions and may limit the clinical utility of these drugs. We have previously shown that systemic gabapentin (GBP), a non-opioid drug, prevents and reverses tolerance to systemic morphine in the rat. In this study, we investigated the effect of intrathecal GBP on spinal morphine tolerance. Studied rats were given 7 days of intrathecal injections with saline (10 microL), GBP (300 microg), morphine (15 microg), or a GBP-morphine combination, and analgesic testing using tail-flick and paw-pressure tests was conducted before and 30 min after the drug injection. On Day 8, an antinociceptive dose-response curve was constructed and the 50% effective dose (ED(50)) values for morphine (given alone) were calculated for each study group. Coinjection of GBP with morphine blocked the development of tolerance, as shown by the preservation of morphine analgesia over 7 days as well as by a concomitant decrease in ED(50) values on Day 8, as compared with the morphine-alone group. Although additive analgesia over Days 1-7 cannot be ruled out, ED(50) reductions in the GBP-morphine combination group indeed suggest some suppression of tolerance. These data support previous evidence that GBP prevents opioid tolerance and, more specifically, indicate that intrathecal GBP prevents the development of spinal opioid tolerance. Future studies are required to examine the respective roles of supraspinal and peripheral sites of GBP-morphine interaction and to investigate the mechanisms underlying the action of GBP on opioid tolerance.
Anesthesiology. 2003 May;98(5):1288-92.
Gabapentin blocks and reverses antinociceptive morphine tolerance in the rat paw-pressure and tail-flick tests.
Gilron I, Biederman J, Jhamandas K, Hong M.
Source
Department of Anesthesiology, Kingston General Hospital Queen's University, Ontario, Canada. [email protected]
PMID: 12717156 [PubMed - indexed for MEDLINE] Free Article
Brain Res. 1999 Jul 10;834(1-2):178-81.
Reversal of morphine tolerance and dependence by melatonin: possible role of central and peripheral benzodiazepine receptors.
Raghavendra V, Kulkarni SK.
Source
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India.
Abstract
Possible reversal by melatonin of morphine-induced tolerance and dependence was studied in mice. A 10-day repeated injection regimen was followed to induce morphine tolerance and dependence. Co-administration of melatonin (1-10 mg/kg, i.p.) with morphine (10 mg/kg, s.c.) during the induction phase (day 1 to 9) reversed the development of opioid tolerance and dependence tested on 10th day. On the other hand acute administration of melatonin (1-10 mg/kg) on the 10th day, ie. during the expression phase of morphine dependence, it reduced the incidence of naloxone-induced withdrawal jumps without affecting the tolerance to analgesic effect. Co-administration of flumazenil (2 mg/kg, i.p.), a central benzodiazepine (BZ) receptor antagonist had no effect on melatonin response, whereas peripheral antagonist for BZ receptor PK11195 (2 mg/kg, i.p.) significantly reversed the attenuating effect of melatonin on physical dependence both during induction and expression phase of morphine tolerance and dependence. These observations suggest that melatonin reverses development of tolerance and dependence to morphine, and this action possibly involved peripheral benzodiazepine receptors.
Copyright 1999 Elsevier Science B.V.
Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice
Purchase
$ 31.50
Joanna Mikaa, Agnieszka Wawrzczak-Bargielab, Maria Osikowicza, Wioletta Makucha and Barbara Przewlockaa, ,
a Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland
b Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland
Received 2 April 2008; revised 14 July 2008; accepted 14 July 2008. Available online 22 July 2008.
Abstract
We have previously demonstrated that glial inhibitors reduce the development of allodynia and hyperalgesia, potentiating the effect of a single morphine dose in a neuropathic pain model. This study explores the effects of two glial activation inhibitors, minocycline and pentoxifylline, on the development of tolerance to morphine in naive and chronic constriction injury (CCI)-exposed mice. Administration of morphine to naive (20 mg/kg; i.p.) and CCI-exposed mice (40 mg/kg; i.p.) twice daily resulted in tolerance to its anti-nociceptive effect after 6 days. Injections of morphine were combined with minocycline (30 mg/kg, i.p.) or pentoxifylline (20 mg/kg, i.p.) administered as two preemptive doses before first morphine administration in naive or pre-injury in CCI-exposed mice, and repeated twice daily 30 min before each morphine administration. With treatment, development of morphine tolerance was delayed by 5 days (from 6 to 11 days), as measured by the tail-flick test in naive and by tail-flick, von Frey, and cold plate tests in CCI-exposed mice. Western blot analysis of CD11b/c and GFAP protein demonstrated that minocycline and pentoxifylline, at doses delaying development of tolerance to morphine analgesia, significantly diminished the morphine-induced increase in CD11b/c protein level. We found that repeated systemic administration of glial inhibitors significantly delays development of morphine tolerance by attenuating the level of this microglial marker under normal and neuropathic pain conditions. Our results support the idea that targeting microglial activation during morphine therapy/treatment is a novel and clinically promising method for enhancing morphine’s analgesic effects, especially in neuropathic pain.
Keywords: Morphine; Tolerance; Pain; Minocycline; Pentoxifylline; Microglia; CD11b/c (OX42); Astrocytes; GFAP; Glia
Brain Res. 1995 Mar 27;675(1-2):31-7.
Inhibition of morphine tolerance and dependence by diazepam and its relation to cyclic AMP levels in discrete rat brain regions and spinal cord.
Sheu MJ, Sribanditmongkol P, Santosa DN, Tejwani GA.
Source
Department of Pharmacology, Ohio State University, College of Medicine, Columbus 43210-1239, USA.
Abstract
Diazepam inhibits morphine tolerance and dependence and reverses a decrease in the met-enkephalin level in brain induced by morphine. In this study, we investigated whether inhibition of morphine-induced tolerance and dependence by diazepam involved a change in cyclic AMP levels in discrete rat brain regions and spinal cord. Male Sprague-Dawley rats were made tolerant and dependent by subcutaneous (s.c.) implantation of six morphine pellets (two pellets on the first day, and four on the second day). Diazepam (0.25 mg/kg b. wt) was injected once daily intraperitoneally (i.p.) for 5 days. Control rats were implanted with placebo pellets and injected once daily with saline or diazepam (i.p.). Tail-flick antinociception was measured 1 h after injections everyday. Animals were administered s.c. naloxone (10 mg/kg) to induce naloxone-precipitated withdrawal syndrome on the final day of the experiment (day 5), and the jumping behavior was observed for 30 min. Concomitant treatment with diazepam (0.25 mg/kg) significantly decreased the development of morphine tolerance and dependence. Diazepam (0.25 mg/kg) treated rats also showed a significant decrease in the jumping behavior compared to animals treated with morphine alone. Rats were sacrificed 2 h after the injection of saline or diazepam (0.25 mg/kg) on the fifth day. Cyclic AMP was estimated by RIA. In the control rats, the concentration of cyclic AMP in cortex was > hippocampus > cerebellum > hypothalamus > striatum > midbrain > pituitary > pons/medulla > spinal cord. There was no change in the concentration of cyclic AMP in any of the brain regions examined from morphine tolerant animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Looks like cafeine is bad for benzo tolerance.Pharmacol Biochem Behav. 2010 Feb;94(4):510-5. Epub 2009 Nov 24.
Adenosinergic system is involved in development of diazepam tolerance in mice.
Listos J, Talarek S, Fidecka S.
Source
Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Staszica 4, 20-081 Lublin, Poland. [email protected]
Abstract
In the present study the effect of adenosinergic system on the development of diazepam tolerance to motor disturbances in mice was investigated. Diazepam tolerance was obtained by administration of diazepam at a dose of 5.0 mg/kg, s.c. for ten consecutive days. On the 1st and the 10th day of the experiment motor impairments were measured in two behavioural tests: rota-rod and chimney test. We showed that acute diazepam injection produced significant motor impairments in mice and that effect was decreased by repeated diazepam treatment, confirming the development of tolerance to the motor impairing effect of diazepam. We demonstrated that adenosine A(1) and/or A(2A) receptor agonists: CPA (0.025 and 0.05 mg/kg, i.p.), CGS 21680 (0.1 and 0.2 mg/kg, i.p.), NECA (0.005 and 0.01 mg/kg, i.p.) pretreatment with diazepam were able to attenuate the development of diazepam tolerance and adenosine receptor antagonists: DPCPX (1.0 and 3.0 mg/kg, i.p.), DMPX (3.0 and 6.0 mg/kg, i.p.) and caffeine (10.0 and 20.0mg/kg, i.p.) induced the opposite effect. The most apparent effects were obtained by non-selective agonist (NECA) and antagonist (caffeine) of adenosine receptors. We conclude that adenosinergic system plays an important role in mechanisms underlying the development of benzodiazepine tolerance.
Arch Pharm Res. 2005 Sep;28(9):995-1001.
Pharmacological action of Panax ginseng on the behavioral toxicities induced by psychotropic agents.
Kim HC, Shin EJ, Jang CG, Lee MK, Eun JS, Hong JT, Oh KW.
Source
Neurotoxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Korea.
Abstract
Morphine-induced analgesia has been shown to be antagonized by ginseng total saponins (GTS), which also inhibit the development of analgesic tolerance to and physical dependence on morphine. GTS is involved in both of these processes by inhibiting morphine-6-dehydrogenase, which catalyzes the synthesis of morphinone from morphine, and by increasing the level of hepatic glutathione, which participates in the toxicity response. Thus, the dual actions of ginseng are associated with the detoxification of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contractions in guinea pig ileum (mu-receptors) and mouse vas deferens (delta-receptors) are not mediated through opioid receptors, suggesting the involvement of non-opioid mechanisms. GTS also attenuates hyperactivity, reverse tolerance (behavioral sensitization), and conditioned place preference induced by psychotropic agents, such as methamphetamine, cocaine, and morphine. These effects of GTS may be attributed to complex pharmacological actions between dopamine receptors and a serotonergic/adenosine A2A/ delta-opioid receptor complex. Ginsenosides also attenuate the morphine-induced cAMP signaling pathway. Together, the results suggest that GTS may be useful in the prevention and therapy of the behavioral side effects induced by psychotropic agents.
J Psychopharmacol. 2011 Mar;25(3):411-20. Epub 2010 Feb 8.Inhibition of morphine tolerance and dependence by Withania somnifera in mice.
Kulkarni SK, Ninan I.
Source
Pharmacology Division, University Institute of Pharmaceutical Sciences, Punjab University, Chandigarh, India.
Abstract
Chronic treatment with Withania somnifera (Ws) (family: Solanaceae, 100 mg/kg) commercial root extract followed by saline on days 1-9 failed to produce any significant change in tailflick latency from the saline pretreated group in mice. However, repeated administration of Ws (100 mg/kg) for 9 days attenuated the development of tolerance to the analgesic effect of morphine (10 mg/kg). Ws (100 mg/kg) also suppressed morphine-withdrawal jumps, a sign of the development of dependence to opiate as assessed by naloxone (2 mg/kg) precipitation withdrawal on day 10 of testing.
[/QUOTE]Effects of a Rhodiola rosea L. extract on acquisition and expression of morphine tolerance and dependence in mice.
Mattioli L, Perfumi M.
Source
Department of Experimental Medicine and Public Health, University of Camerino, via Madonna delle Carceri, 62032 Camerino, Italy.
Abstract
This study investigated the effect of Rhodiola rosea L. extract on acquisition and expression of morphine tolerance and dependence in mice. Therefore animals were injected with repeated administration of morphine (10 mg/kg, subcutaneous) twice daily for five or six days, in order to make them tolerant or dependent. Rhodiola rosea L. extract (0, 10, 15 and 20 mg/kg) was administered by the intragastric route 60 min prior to each morphine injection (for acquisition) or prior the last injection of morphine or naloxone on test day (for tolerance or dependence expression, respectively). Morphine tolerance was evaluated by testing its analgesic effect in the tail flick test at the 1st and 5th days. Morphine dependence was evaluated by counting the number of withdrawal signs (jumping, rearing, forepaw tremor, teeth chatter) after naloxone injection (5 mg/kg; intraperitoneal) on the test day (day 6). Results showed that Rhodiola rosea L. extract significantly reduced the expression of morphine tolerance, while it was ineffective in modulating its acquisition. Conversely, Rhodiola rosea L. extract significantly and dose-dependently attenuated both development and expression of morphine dependence after chronic or acute administration. These data suggest that Rhodiola rosea L. may have human therapeutic potential for treatment of opioid addiction.
Ultra low dose naltrexone and proglumide are also 2 compounds id like to see discussed here.
D aspartic acid
It appears that someone reported D aspartic acid to reverse ketamine tolerance, besides that he said it worked agains tolerance to other drugs too.
While it appears to act as a glutamate agonist, this experience combined with my own experience adding it to memantine makes me think it somehow downregulate the NMDA receptors, the reason being that in my experience it reversed the memantine adaptation period (the cognitive effects wich imo go away because during the adaptation phase the NMDA receptors partionally upregulate). It would make sense as NMDA downregulation explains ketamine tolerance reversal and also tolerance reversal to all other drugs nmda antagonists are effective for.
For more info about D aspartic acid:
http://www.ergo-log.com/dasparticacidtestosterone.html
Its been discussed on fora like bodybuilding.com because it raises testosterone quite a bit.
(This is only based on one anecdotal report).
Cheers.
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