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S-adenosyl methionine (SAM) attenuates the development of tolerance to analgesic activity of morphine in rats
Neuroscience Letters 645 (2017) 67–73
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research article
S-adenosyl methionine (SAM) attenuates the development of tolerance to analgesic activity of morphine in rats Jatinder Katyal, Hemant Kumar, Dinesh Joshi, Yogendra Kumar Gupta ∗ Department of Pharmacology, AIIMS, New Delhi 110029, India
h i g h l i g h t s • S-adenosyl methionine (SAM) reversed tolerance to morphine analgesia in tail flick test in rats. • Repeated SAM per se dosing showed analgesic activity which was reversed by naloxone. • Combining SAM with sub therapeutic dose of morphine also attenuated SAM analgesia.
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Article history: Received 22 November 2016 Received in revised form 16 February 2017 Accepted 20 February 2017 Available online 22 February 2017 Keywords: S-adenosylmethionine (SAM) Morphine Tolerance Pain Tail flick latency
a b s t r a c t Background: Development of tolerance to analgesic effect, on chronic administration of morphine, limits its clinical usefulness in pain management. S-adenosyl methionine (SAM) used for arthritis and approved as a supplement in many countries including United States was evaluated for reducing morphine tolerance. Methods: Male ‘Wistar’ rats were used. The analgesic activity was determined using tail flick analgesiometer (Columbus Instruments, USA). Rats given morphine (7 mg/kg), intraperitoneally (i.p.), once daily for 5 days developed tolerance to analgesic effect. To evaluate the effect of SAM on morphine tolerance, SAM 800 mg/kg was administered orally (p.o.), 45 min prior to each dose of morphine. The analgesic activity of SAM and opioidergic component in its activity was also evaluated. Results: Co-administration of morphine and SAM reversed morphine tolerance. SAM exhibited analgesic effect after repeated administration which was reversed by naloxone administration. Conclusion: Since safety of SAM on chronic use is documented it can be a good option in morphine tolerance. Role in drug addiction and withdrawal should also be evaluated. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Development of tolerance and therefore need of increased dose of morphine for management of severe pain has been an important limitation. Various hypotheses for morphine tolerance have been proposed. These include, phosphorylation of opioid receptor and receptor desensitization [1], -opioid receptor internalization [2], up regulation of the cAMP pathway and P-gp transporter [3]. Besides, various receptors and effectors may also be involved in mediating morphine tolerance like N-methyl D-aspartate (NMDA) [4], orexin [5], toll like receptor [6], protein kinase C (PKC), calcium and calmodulin-dependent kinase II (CAMK II) [4,7], betaarrestin [8], mitogen-activated protein kinases (MAPKs), matrix metalloproteinase-9 (MMP-9) [9] and oxidative stress [10]. A
∗ Corresponding author. E-mail address: [email protected] (Y.K. Gupta). http://dx.doi.org/10.1016/j.neulet.2017.02.054 0304-3940/© 2017 Elsevier B.V. All rights reserved.
reduction of morphine tolerance has been reported with drugs like, pioglitazone [11], lamotrigine [12], haloperidol [13], trifluperazine [14], etc. However, these drugs are known to have their own side effects and safer options are needed. Recently, it has been shown that chronic morphine administration inhibits excitatory amino acid transporter-3 (EAAT-3) causing a decrease in cysteine uptake and impaired redox status which in turn alters DNA methylation capacity of cell leading to morphine tolerance and addiction [15–18]. This would imply that maintaining the methylation capacity would reverse the morphine tolerance. An important player in methylation reaction is s-adenosyl methionine (SAM) [19]. Levels of SAM have been directly linked with methylation capacity [20]. Interestingly, SAM is known to have an antiarthritic [21] and antidepressant activity [22]. It is categorised under vitamins and supplements by the US FDA and is also available in many countries [23]. In osteoarthritis, effect of SAM has been compared with that of piroxicam, ibuprofen and celecoxib [21]. Therefore, in this study we determined the effect
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Fig. 1. Experimental protocol. (A) Effect of SAM on morphine tolerance (B) Mechanistic study to determine role of opioid receptor in SAM analgesia. Tail flick latencies were determined daily from day1 to day 5 between 10:00 h-13:00 h. * − Concurrent vehicle controls were run for each group. For SAM group vehicle was administered 90 min before while for morphine group 45 min before TFL. # − Dose and time to peak effect were determined in our pilot studies. @ − Naloxone was administered 30 min before determination of TFLs on all days. The pretreatment times for morphine and SAM were the same ie. 45 min and 90 min respectively.
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Fig. 2. Effect of morphine daily administration on analgesic activity. Morphine was administered at a dose of 7 mg/kg, i.p., daily for five days and TFLs were noted at 45 min. Results are presented as% MPE. The box represents the interquartile range, the line within is the median and ends of the ‘whiskers’ show maximum and minimum (n = 6). a- as compared to vehicle control, **p < 0.01. CON-Vehicle control; MOR7-Morphine 7 mg/kg.
Fig. 4. (a) Effect of opioid antagonist naloxone 0.5 mg/kg pre-treatment on analgesic effect of SAM 800 mg/kg. (b) Effect of co-administration of SAM (800 mg/kg) with subanalgesic dose of morphine (3 mg/kg) on TFL (n = 6). a-as compared to vehicle control; b-as compared to SAM 800 mg/kg. *p < 0.05. CON-Vehicle control; MOR3Morphine 3 mg/kg; SAM 800- S-adenosyl methionine 800 mg/kg; NAL 0.5-Naloxone 0.5 mg/kg. Results are presented as% MPE. The box represents the interquartile range, the line within is the median and ends of the ‘whiskers’ show maximum and minimum.
Fig. 3. Effect of SAM (800 mg/kg), morphine (7 mg/kg) and SAM plus Morphine on TFLs. Morphine was administered 45 min after SAM. Tail flick latency was taken at 90 min after SAM. Results are presented as% MPE. The box represents the interquartile range, the line within is the median and ends of the ‘whiskers’ show maximum and minimum (n = 6). a- compared to vehicle control; ***p < 0.001; **p < 0.01; *p < 0.05. CON-Vehicle control; MOR7-Morphine 7 mg/kg; SAM 800- Sadenosyl methionine 800 mg/kg.
of co-administration of SAM with morphine on development of morphine tolerance using tail flick latency (TFL) test in rats. 2. Materials and methods 2.1. Experimental animals All experimental procedures were carried out after being approved by the Institutional Animal Ethics Committee (IAEC), AIIMS (ethics approval no. 871/IAEC/15). Male Wistar rats, 200–260 g were used for the study. Animals were obtained from the Central Animal Facility of AIIMS, New Delhi, India. The rats were housed in polypropylene cages containing paddy husk, in groups of 3 per cage, at ambient temperature (22–25 C), 12 h light/dark cycles and were allowed free access to rat pellet diet (M/s Ashirwad Industries, Chandigarh) and tap water. Food was withheld 3 h before experimentation as food is known to interfere with absorption of SAM. The rats were acclimatized to laboratory conditions
7 days prior to experimentation. All experiments were carried out between 10:00 A.M.–1:00 P.M. and experimental procedures were in accordance with INSA guidelines on use of animals in research. After the completion of the study, rats were rehabilitated in the central animal care facility, AIIMS, New Delhi, India. After excluding rats not meeting the inclusion criteria (TFLs between 4.0–8.0), all groups comprised of 6 rats. 2.2. Drugs and treatment schedules Pure S-adenosylmethionine (SAM) was obtained as gift from Wockhardt Limited, India. SAM was dissolved in double distilled water, using orbital shaker. SAM was prepared freshly before administration every day. Morphine was obtained from Verve Human Care laboratories, Dehradun, India. Naloxone was obtained from Samarth life Sciences Pvt. Ltd. India. Refer Fig. 1 for experimental protocol and timelines of the study. 2.3. Determination of tail flick latency (TFL) Tail flick analgesiometer, (Columbus Instruments, USA) was used to induce pain by heat stimulus as described by us earlier [24,25]. Briefly, a constant intensity heat stimulus was applied on the distal portion of the tail, 3 cm from the apex and tail flick latencies (TFLs) were recorded. The heat intensity was set to obtain the
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2.7. Determination of role of opioid receptor in analgesic effect of SAM 2.7.1. Effect of naloxone In this set of experiments, rats were administered naloxone 0.5 mg/kg, i.p., 60 min after SAM 800 mg/kg, p.o., for five days. Tail flick latencies were noted on all days, 90 min after SAM administration. 2.7.2. Effect of combination of sub analgesic dose of morphine (3 mg/kg) and SAM (800 mg/kg) to rule out an additive effect Rats were divided into three groups and received vehicle, morphine in sub analgesic dose (3 mg/kg, i.p.) and combination of SAM (800 mg/kg) and sub analgesic dose of morphine daily for five days. Morphine was administered 45 min after SAM administration and TFLs were taken at 90 min after SAM administration. 2.8. Statistical analysis Fig. 5. Proposed transport mechanism of SAM into brain after oral administration in rats. A-Methyl transferases; B-SAM hydrolase; C-␥-cystathionase; D-methionine adenosyltransferase; E-Methionine synthases; SAH- S-adenosine homocysteine;SAM-S-adenosine methionine; GIT-Gastro intestinal tract.
The latencies were converted to percent maximal possible effect (% MPE), calculated as − %MPE =
baseline TFLs ≤ 8.0 s. Any animal showing baseline value greater than 8.0 s was not included. During experimentation, a cut-off time of double the baseline was used to avoid injury to the rats.
2.4. Determination of peak effect of SAM and morphine on analgesic activity using tail flick test in rats Rats were divided into three groups, vehicle control, SAM 400 and 800 mg/kg. SAM was administered orally by gavage, this being the intended route for clinical use and tail flick latencies were taken every 30 min upto 2 h. A single dose of SAM did not show any analgesic effect with any of the dose used (data not shown). However, 800 mg/kg on repetitive dosing exhibited an analgesic effect on day 5. Hence SAM 800 mg/kg was used for further experiments. In a separate group of rats, morphine at 7.0 mg/kg, i.p. was administered and tail flick latencies were taken every 15 min up to 2 h. The SAM peak was seen at 90 min while morphine effect peaked at 45 min (data not shown). For further experiments, TFLs were determined at 45 and 90 min after morphine and SAM administration respectively.
2.5. Development of morphine tolerance using tail flick test in rats Rats were divided into two groups and received vehicle or morphine at 7 mg/kg. Morphine was administered daily for five days followed by determination of TFL at 45 min, since the peak effect was at this time point.
(Post treatment latency-Pretreatment latency) × 100 Pretreatment latency
The analyses of data were performed by an observer naïve to study groups. Levene, s test was used to determine homogeneity of variances. Since all data was nonparametric, Mann Whitney, Kruskal Wallis and chi square tests were used. Dunn’s posthoc test was used to determine significance between groups. The ␣ level was set at 0.05. STATA 10 software was used for data analysis. In the figures, % MPE is plotted vs number of days as box plots. The box represents the interquartile range, the line within the box is the median. The ends of the ‘whiskers’ show maximum and minimum values. 3. Results The baseline tail flick latencies were not significantly different among different groups. 3.1. Development of tolerance with morphine Morphine at 7 mg/kg, i.p., showed the highest analgesic activity on day 1 (p-value = 0.0022, Mann-Whitney u = 0.0000; median = 100.0 vs control 7.58; minimum and maximum values 65.67 and 100.0 vs control −18.82 and 19.43 respectively) after which the analgesia declined. The median values for morphine being 39.63, 37.31, 0.27, 13.19 vs 15.10, −1.69, 6.93, 8.95 for control from days 2–5 respectively. TFLs for morphine and vehicle control were not significantly different at day 4 and 5 (p-value = 0.3939 and 0.8182; Mann-Whitney u = 12.00 and 16.00 on day 4 and 5 respectively) (Fig. 2).
2.6. Determination of effect of SAM co-administration with morphine on morphine tolerance using tail flick test in rats
3.2. Effect of SAM (800 mg/kg, po) and morphine (7 mg/kg, ip) co-administration on morphine tolerance
Rats were divided into four groups, vehicle control, SAM 800 mg/kg, morphine 7 mg/kg and their combination i.e. SAM 800 mg/kg + morphine 7 mg/kg. Morphine was administered after 45 min of SAM administration and TFL was taken after 90 min of SAM administration every day. This protocol was followed for 5 days (Refer Fig. 1).
Co-administering SAM at 800 mg/kg, p.o., 45 min before morphine administration reversed the morphine tolerance and a statistically significant analgesic effect was maintained on all days (Day 1–5) (p-values: 0.0001, 0.0017, 0.0002; 0.0001 and 0.0001; chi-sqr = 19.651, 18.883, 18.127, 17.033 and 18.313; d.f. = 3 from day 1–5 respectively) (Fig. 3).
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Fig. 6. Proposed mechanism of reversal of morphine tolerance. Chronic morphine administration blocks the influx of cysteine and alters the SAM levels and epigenetic expression, resulting in morphine tolerance. Exogenous SAM administration would replenish the SAM levels and therefore may reverse the morphine tolerance. SAM-Sadenosyl methionine; EAAT3-Excitatory amino acid transporter 3.
3.3. Effect of opioid receptor antagonist naloxone on analgesic effect of SAM Naloxone at 0.5 mg/kg, i.p., had no significant effect on TFLs but when naloxone was administered with SAM, it significantly antagonized the analgesic effect of SAM on TFLs (Fig. 4a) (NC vs SAM or SAM + NAL p-value = 0.0075 and 1.0000; chi-sqr = 12.69; d.f.=3; median, minimum and maximum values −8.988, −30.84 and 14.69 vs 33.37, 25.53 and 51.02 respectively). 3.4. Interaction of SAM (800 mg/kg, po) with sub analgesic dose of morphine (3 mg/kg, ip) Daily administration of morphine at sub analgesic dose (3 mg/kg, i.p.) showed no analgesic effect. Co-administration of SAM at 800 mg/kg, p.o., showed no additive effect on TFLs rather the analgesic effect of SAM was also not seen (Day 5, NC vs SAM or NC vs SAM + MOR3, p-value = 0.0112 and 0.8648 respectively; chi-sqr = 10.763; d.f. = 3) (Fig. 4b). 4. Discussion Tolerance to morphine is a major limitation in its use as an analgesic. This tolerance to morphine can develop even after a single dose [26]. In our study as well, antinociceptive activity of morphine declined from day 2 onwards. Multiple mechanisms and effectors have been implicated in opioid tolerance and dependence. Garzon et al. [27] suggest that in order to diminish tolerance it is crucial to identify additional links. S-adenosyl-l-methionine (SAM) is a nutraceutical, with clinically demonstrated efficacy and safety in osteoarthritis [28]. Mechanistically, SAM is involved in three major biochemical pathways −transsulfuration, aminopropylation and methylation, which, in turn can potentially modulate inflammatory mediators, proteoglycan synthesis, cell signalling, glutathione levels and DNA
methylation [29]. We evaluated usefulness of SAM in morphine tolerance using tail flick latency test in rats. Tail-flick in rodents involves a spinal nociceptive reflex and the reaction times are used for evaluating analgesic activity. The human equivalent dose of SAM (200 mg/kg), did not show any analgesic activity in pilot study therefore, higher doses of SAM, (400 and 800 mg/kg, p.o.) were also evaluated. A single dose of SAM did not show any analgesic effect at any of the dose used. However, 800 mg/kg on repetitive dosing exhibited an analgesic effect. The maximum analgesic activity of SAM was observed at 90 min which is in agreement with previous reports [23]. The efficacy after repeated daily dosing and with higher doses is likely due to the intricate feedback regulation of SAM levels in the body via the methionine cycle (Fig. 5). On exogenous administration, the excess SAM is converted to methionine which can cross the blood brain barrier freely unlike SAM which does so poorly. The methionine that crosses to brain could be contributing to the analgesic activity directly or via conversion to SAM within the brain. An analgesic activity with methionine has been reported [23]. However, time to peak analgesic activity (90 min) is more in line with the effect being due to SAM rather than methionine. The mechanism of analgesic activity of SAM has not been worked out. We evaluated the role of opioid receptors in the analgesic activity of SAM using naloxone an opioid receptor antagonist. Naloxone significantly attenuated the analgesic activity of SAM suggesting an interaction between SAM and opioidergic system. At the same time combination of low dose morphine and SAM 800 mg/kg did not show any additive effect rather, the effect of SAM was attenuated. Opposing effects of different doses of morphine with acute administration have been reported previously, [30,31], but these cannot explain our results as we have used a repeated dosing protocol. It is likely that SAM shows analgesia by facilitating endogenous opioids. Repeated administrations of morphine 3 mg/kg would results in downregulation of opioidergic receptors and therefore attenuated SAM analgesia. The combination of mor-
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phine 7 mg/kg with SAM could also have attenuated the analgesic effect of SAM but the attenuation of SAM analgesia was masked by analgesic effect due to reversal of morphine tolerance. It has been previously proposed that opioid-induced adaptations occur at different levels in the nervous system [27]. Recently, Trivedi and Deth [18] have proposed that morphine tolerance and addiction may be due to epigenetic changes which are mediated to some extent by change in methylation status. In their studies using neuronal cell culture, morphine via mu receptors inhibited excitatory amino acid transporter-3(EAAT-3), mediated cysteine uptake. The cysteine uptake has been associated with alterations in redox status, glutathione levels and DNA methylation [17]. As hypothesised, the exogenous SAM co-administration attenuated morphine tolerance (Refer Fig. 6).
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[5]
[6]
[7]
[8]
4.1. Limitations A limitation of this study could be high inter-animal variability with opioidergic interventions. Also, since the study was planned as a proof of concept in intact animal, simultaneous mechanistic/biochemical determinations have not been carried out. It is therefore not possible to exclude any off target effect of SAM given the high dose used or any other hitherto unknown effect for reversing morphine tolerance.
[9]
[10]
[11]
4.2. Conclusion and future directions These results have implication not only for preventing morphine tolerance but also SAM can be explored in drug addiction and withdrawal. Besides, a detailed study of locus and biochemical mechanisms involved at molecular level can also yield valuable information and further targets. Conflict of interest statement The authors declare no conflicts of interest.
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[13]
[14]
[15] [16]
Authors contribution Jatinder Katyal: Substantial contribution to concept, design, interpretation of data, drafting, revision and final approval of the manuscript. Hemant Kumar: Substantial contribution to concept, design, acquisition, analysis, drafting, revision and interpretation of data, and final approval of the manuscript. Dinesh Joshi: Substantial contribution to design and acquisition of data and final approval of the manuscript. Yogendra Kumar Gupta: Substantial contribution to concept, interpretation of data, drafting, revision and final approval of the manuscript.
[17]
[18]
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[20] [21]
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.neulet.2017.02. 054.
[22]
References
[24]
[1] J.T. Williams, S.L. Ingram, G. Henderson, C. Chavkin, M. von Zastrow, S. Schulz, T. Koch, C.J. Evans, M.J. Christie, Regulation of -opioid receptors: desensitization, phosphorylation, internalization, and tolerance, Pharmacol. Rev. 15 (2013) 223–254, http://dx.doi.org/10.1124/pr.112.005942. [2] B.L. Kieffer, C.J. Evans, Opioid tolerance-in search of the holy grail, Cell 8 (2002) 587–590, http://dx.doi.org/10.1016/s0092-8674(02)00666-9. [3] S.L. Mercer, A. Coop, Opioid analgesics and P-glycoprotein efflux transporters: a potential systems-level contribution to analgesic tolerance, Curr. Top. Med.
[23]
[25]
[26]
Chem. 11 (2011) 1157–1164, http://dx.doi.org/10.2174/ 156802611795371288. ˜ M. Rodríguez-Munoz, J. Garzón, Nitric oxide and zinc-mediated protein assemblies involved in mu opioid receptor signalling, Mol. Neurobiol. 48 (2013) 769–782, http://dx.doi.org/10.1007/s12035-013-8465-z. E. Erami, H. Azhdari-Zarmehri, A. Rahmani, E. Ghasemi-Dashkhasan, S. Semnanian, A. Haghparast, Blockade of orexin receptor 1 attenuates the development of morphine tolerance and physical dependence in rats, Pharmacol. Biochem. Behav. 103 (2012) 212–219, http://dx.doi.org/10.1016/j. pbb.2012.08.010. L.N. Eidson, A.S. Murphy, Blockade of toll-like receptor 4 attenuates morphine tolerance and facilitates the pain relieving properties of morphine, J. Neurosci. 33 (2013) 15952–15963. ˜ P. Sánchez-Blázquez, M. Rodríguez-Munoz, E. Berrocoso, J. Garzón, The plasticity of the association between mu-opioid receptor and glutamate ionotropic receptor N in opioid analgesic tolerance and neuropathic pain, Eur. J. Pharmacol. 716 (2013) 94–105, http://dx.doi.org/10.1016/j.ejphar.2013.01. 066. L.M. Bohn, R.R. Gainetdinov, F. Lin, R.J. Lefkowitz, M.G. Caron, Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence, Nature 408 (2000) 720–723, http://dx.doi.org/10.1038/ 35047086. K. Nakamoto, S. Kawasaki, T. Kobori, W. Fujita-Hamabe, H. Mizoguchi, K. Yamada, T. Nabeshima, S. Tokuyama, Involvement of matrix metalloproteinase-9 in the development of morphine tolerance, Eur. J. Pharmacol. 683 (2012) 86–92, http://dx.doi.org/10.1016/j.ejphar.2012.03.006. J.W. Little, S. Cuzzocrea, L. Bryant, E. Esposito, T. Doyle, S. Rausaria, W.L. Neumann, D. Salvemini, Spinal mitochondrial-derived peroxynitrite enhances neuroimmune activation during morphine hyperalgesia and antinociceptive tolerance, Pain 154 (2013) 978–986, http://dx.doi.org/10.1016/j.pain.2013.02. 018. H. Ghavimi, M. Charkhpour, S. Ghasemi, M. Mesgari, H. Hamishehkar, K. Hassanzadeh, S. Arami, K. Hassanzadeh, Pioglitazone prevents morphine antinociceptive tolerance via ameliorating neuroinflammation in rat cerebral cortex, Pharmacol. Rep. 67 (2015) 78–84, http://dx.doi.org/10.1016/j.pharep. 2014.08.003. G. Jun, S.H. Kim, Y.I. Yoon, J.Y. Park, Intrathecal lamotrigine attenuates antinociceptive morphine tolerance and suppresses spinal glial cell activation in morphine-tolerant rats, J. Korean Med. Sci. 28 (2013) 300–307, http://dx. doi.org/10.3346/jkms.2013.28.2.300. C. Yang, Y. Chen, L. Tang, Z.J. Wang, Haloperidol disrupts opioid-antinociceptive tolerance and physical dependence, J. Pharmacol. Exp. Ther. 338 (2011) 164–172, http://dx.doi.org/10.1124/jpet.110.175539. L. Tang, P.K. Shukla, Z.J. Wang, Trifluoperazine, an orally available clinically used drug, disrupts opioid antinociceptive tolerance, Neurosci. Lett. 397 (2006) 1–4, http://dx.doi.org/10.1016/j.neulet.2005.11.050. M.S. Trivedi, N.W. Hodgson, J.S. Shah, R.C. Deth, A novel redox based epigenetic signalling mechanism for opioids, FASEB J. 27 (2013) 1180–1188. M.S. Trivedi, J.S. Shah, N.W. Hodgson, H.M. Byun, R.C. Deth, Morphine induced redox based changes in global DNA methylation and retrotransposon transcription by inhibition of excitatory amino acid transporter type 3-mediated cysteine uptake, Mol. Pharmacol. 85 (2014) 747–757, http://dx. doi.org/10.1124/mol.114.091728. M.S. Trivedi, J.S. Shah, S. Al-Mughairy, N.W. Hogdson, B. Simms, G.A. Troosken, W.V. Creikinge, R.C. Deth, Food derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences, J. Nutr. Biochem. 25 (2014) 1011–1018, http://dx.doi.org/10.1016/j.jnutbio.2014.05.004. M.S. Trivedi, R.C. Deth, Redox based epigenetic status in drug addiction: a potential contributor to gene priming and a mechanistic rationale for metabolic intervention, Front. Neurosci. 8 (2015) 1–13, http://dx.doi.org/10. 3389/fnins.2014.00444. P.K. Chiang, R.K. Gordon, J. Tal, G.C. Zeng, B.P. Doctor, K. Pardhasaradhi, P.P. McCann, S-Adenosyl methionine and methylation, FASEB J. 10 (1996) 471–480. J.M. Mato, S.C. Lu, Role of S-adenosyl-L-methionine in liver health and injury, Hepatology 45 (2007) 1306–1312, http://dx.doi.org/10.1002/hep.21650. W.I. Najm, S. Reinsch, F. Hoehler, J.S. Tobis, P.W. Harvey, S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial, BMC Musculoskelet Disord. 26 (2004) 5–6, http://dx.doi.org/10.1186/ISRCTN36233495. D. Mischoulon, M. Fava, Role of S-adenosyl methionine in the treatment of depression: a review of the evidence, Am. J. Clin. Nutr. 76 (2002) 1158S–1161S. S.N. Young, M. Shalchi, The effect of methionine and S-Adenosylmethionine on S-adenosylmethionine levels in the rat brain, Rev. Psychiatr. Neurosci. 30 (2005) 44–48. J. Katyal, Y.K. Gupta, Dopamine release is involved in antinociceptive effect of theophylline, Int. J. Neurosci. 122 (2012) 17–21, http://dx.doi.org/10.3109/ 00207454.2011.613550. J. Malhotra, G. Chaudhary, Y.K. Gupta, Dopaminergic involvement in adenosine A1 receptor mediated antinociception in tail flick latency model in mice, Methods Find. Exp. Clin. Pharmacol. 22 (2000) 37–41, http://dx.doi.org/ 10.1358/mf.2000.22.1.795826. F. Ferrini, T. Trang, T.A. Mattioli, S. Laffray, T. Del’Guidice, L. Lorenzo, A. Castonguay, N. Doyon, W. Zhang, A. Godin, D. Mohr, S. Beggs, K. Vandal, J. Beaulieu, C.C. Cahill, M.W. Salter, Y.D. Koninch, Morphine hyperalgesia gated
J. Katyal et al. / Neuroscience Letters 645 (2017) 67–73 through microglia mediated disruption of Cl− homeostasis, Nat. Neurosci. 16 (2013) 182–193, http://dx.doi.org/10.1038/nn.3295. ˜ P. Sánchez-Blázquez, Do pharmacological [27] J. Garzón, M. Rodríguez-Munoz, approaches that prevent opioid tolerance target different elements in the same regulatory machinery, Curr. Drug Abuse Rev. 1 (2008) 222–238. [28] De Silva, A. El-Metwally, E. Ernst, G. Lewith, G.J. Macfarlane, Evidence for the efficacy of complementary and alternative medicines in the management of osteoarthritis: a systematic review, Rheumatology 50 (2011) 911–920, http:// dx.doi.org/10.1093/rheumatology/keq379.
73
[29] H.J. Blewett, Exploring the mechanisms behind S- adenosylmethionine (SAMe) in the treatment of osteoarthritis, Crit. Rev. Food Sci. Nutr. 48 (2008) 458–463, http://dx.doi.org/10.1080/10408390701429526. [30] Y.K. Gupta, A. Chugh, S.D. Seth, Opposing effect of apomorphine on antinociceptive activity of morphine: a dose-dependent phenomenon, Pain 36 (1989) 263–269, http://dx.doi.org/10.1016/0304-3959(89)90032-8. [31] M.R. Zarrindast, E. Moghaddampour, Opposing influences of D-1 and D-2 dopamine receptors activation on morphine-induced antinociception, Arch. Int. Pharmacodyn. Ther. 300 (1989) 37–50.
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Research article
S-adenosyl methionine (SAM) attenuates the development of tolerance to analgesic activity of morphine in rats Jatinder Katyal, Hemant Kumar, Dinesh Joshi, Yogendra Kumar Gupta ∗ Department of Pharmacology, AIIMS, New Delhi 110029, India
h i g h l i g h t s • S-adenosyl methionine (SAM) reversed tolerance to morphine analgesia in tail flick test in rats. • Repeated SAM per se dosing showed analgesic activity which was reversed by naloxone. • Combining SAM with sub therapeutic dose of morphine also attenuated SAM analgesia.
a r t i c l e
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Article history: Received 22 November 2016 Received in revised form 16 February 2017 Accepted 20 February 2017 Available online 22 February 2017 Keywords: S-adenosylmethionine (SAM) Morphine Tolerance Pain Tail flick latency
a b s t r a c t Background: Development of tolerance to analgesic effect, on chronic administration of morphine, limits its clinical usefulness in pain management. S-adenosyl methionine (SAM) used for arthritis and approved as a supplement in many countries including United States was evaluated for reducing morphine tolerance. Methods: Male ‘Wistar’ rats were used. The analgesic activity was determined using tail flick analgesiometer (Columbus Instruments, USA). Rats given morphine (7 mg/kg), intraperitoneally (i.p.), once daily for 5 days developed tolerance to analgesic effect. To evaluate the effect of SAM on morphine tolerance, SAM 800 mg/kg was administered orally (p.o.), 45 min prior to each dose of morphine. The analgesic activity of SAM and opioidergic component in its activity was also evaluated. Results: Co-administration of morphine and SAM reversed morphine tolerance. SAM exhibited analgesic effect after repeated administration which was reversed by naloxone administration. Conclusion: Since safety of SAM on chronic use is documented it can be a good option in morphine tolerance. Role in drug addiction and withdrawal should also be evaluated. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Development of tolerance and therefore need of increased dose of morphine for management of severe pain has been an important limitation. Various hypotheses for morphine tolerance have been proposed. These include, phosphorylation of opioid receptor and receptor desensitization [1], -opioid receptor internalization [2], up regulation of the cAMP pathway and P-gp transporter [3]. Besides, various receptors and effectors may also be involved in mediating morphine tolerance like N-methyl D-aspartate (NMDA) [4], orexin [5], toll like receptor [6], protein kinase C (PKC), calcium and calmodulin-dependent kinase II (CAMK II) [4,7], betaarrestin [8], mitogen-activated protein kinases (MAPKs), matrix metalloproteinase-9 (MMP-9) [9] and oxidative stress [10]. A
∗ Corresponding author. E-mail address: [email protected] (Y.K. Gupta). http://dx.doi.org/10.1016/j.neulet.2017.02.054 0304-3940/© 2017 Elsevier B.V. All rights reserved.
reduction of morphine tolerance has been reported with drugs like, pioglitazone [11], lamotrigine [12], haloperidol [13], trifluperazine [14], etc. However, these drugs are known to have their own side effects and safer options are needed. Recently, it has been shown that chronic morphine administration inhibits excitatory amino acid transporter-3 (EAAT-3) causing a decrease in cysteine uptake and impaired redox status which in turn alters DNA methylation capacity of cell leading to morphine tolerance and addiction [15–18]. This would imply that maintaining the methylation capacity would reverse the morphine tolerance. An important player in methylation reaction is s-adenosyl methionine (SAM) [19]. Levels of SAM have been directly linked with methylation capacity [20]. Interestingly, SAM is known to have an antiarthritic [21] and antidepressant activity [22]. It is categorised under vitamins and supplements by the US FDA and is also available in many countries [23]. In osteoarthritis, effect of SAM has been compared with that of piroxicam, ibuprofen and celecoxib [21]. Therefore, in this study we determined the effect
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Fig. 1. Experimental protocol. (A) Effect of SAM on morphine tolerance (B) Mechanistic study to determine role of opioid receptor in SAM analgesia. Tail flick latencies were determined daily from day1 to day 5 between 10:00 h-13:00 h. * − Concurrent vehicle controls were run for each group. For SAM group vehicle was administered 90 min before while for morphine group 45 min before TFL. # − Dose and time to peak effect were determined in our pilot studies. @ − Naloxone was administered 30 min before determination of TFLs on all days. The pretreatment times for morphine and SAM were the same ie. 45 min and 90 min respectively.
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Fig. 2. Effect of morphine daily administration on analgesic activity. Morphine was administered at a dose of 7 mg/kg, i.p., daily for five days and TFLs were noted at 45 min. Results are presented as% MPE. The box represents the interquartile range, the line within is the median and ends of the ‘whiskers’ show maximum and minimum (n = 6). a- as compared to vehicle control, **p < 0.01. CON-Vehicle control; MOR7-Morphine 7 mg/kg.
Fig. 4. (a) Effect of opioid antagonist naloxone 0.5 mg/kg pre-treatment on analgesic effect of SAM 800 mg/kg. (b) Effect of co-administration of SAM (800 mg/kg) with subanalgesic dose of morphine (3 mg/kg) on TFL (n = 6). a-as compared to vehicle control; b-as compared to SAM 800 mg/kg. *p < 0.05. CON-Vehicle control; MOR3Morphine 3 mg/kg; SAM 800- S-adenosyl methionine 800 mg/kg; NAL 0.5-Naloxone 0.5 mg/kg. Results are presented as% MPE. The box represents the interquartile range, the line within is the median and ends of the ‘whiskers’ show maximum and minimum.
Fig. 3. Effect of SAM (800 mg/kg), morphine (7 mg/kg) and SAM plus Morphine on TFLs. Morphine was administered 45 min after SAM. Tail flick latency was taken at 90 min after SAM. Results are presented as% MPE. The box represents the interquartile range, the line within is the median and ends of the ‘whiskers’ show maximum and minimum (n = 6). a- compared to vehicle control; ***p < 0.001; **p < 0.01; *p < 0.05. CON-Vehicle control; MOR7-Morphine 7 mg/kg; SAM 800- Sadenosyl methionine 800 mg/kg.
of co-administration of SAM with morphine on development of morphine tolerance using tail flick latency (TFL) test in rats. 2. Materials and methods 2.1. Experimental animals All experimental procedures were carried out after being approved by the Institutional Animal Ethics Committee (IAEC), AIIMS (ethics approval no. 871/IAEC/15). Male Wistar rats, 200–260 g were used for the study. Animals were obtained from the Central Animal Facility of AIIMS, New Delhi, India. The rats were housed in polypropylene cages containing paddy husk, in groups of 3 per cage, at ambient temperature (22–25 C), 12 h light/dark cycles and were allowed free access to rat pellet diet (M/s Ashirwad Industries, Chandigarh) and tap water. Food was withheld 3 h before experimentation as food is known to interfere with absorption of SAM. The rats were acclimatized to laboratory conditions
7 days prior to experimentation. All experiments were carried out between 10:00 A.M.–1:00 P.M. and experimental procedures were in accordance with INSA guidelines on use of animals in research. After the completion of the study, rats were rehabilitated in the central animal care facility, AIIMS, New Delhi, India. After excluding rats not meeting the inclusion criteria (TFLs between 4.0–8.0), all groups comprised of 6 rats. 2.2. Drugs and treatment schedules Pure S-adenosylmethionine (SAM) was obtained as gift from Wockhardt Limited, India. SAM was dissolved in double distilled water, using orbital shaker. SAM was prepared freshly before administration every day. Morphine was obtained from Verve Human Care laboratories, Dehradun, India. Naloxone was obtained from Samarth life Sciences Pvt. Ltd. India. Refer Fig. 1 for experimental protocol and timelines of the study. 2.3. Determination of tail flick latency (TFL) Tail flick analgesiometer, (Columbus Instruments, USA) was used to induce pain by heat stimulus as described by us earlier [24,25]. Briefly, a constant intensity heat stimulus was applied on the distal portion of the tail, 3 cm from the apex and tail flick latencies (TFLs) were recorded. The heat intensity was set to obtain the
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2.7. Determination of role of opioid receptor in analgesic effect of SAM 2.7.1. Effect of naloxone In this set of experiments, rats were administered naloxone 0.5 mg/kg, i.p., 60 min after SAM 800 mg/kg, p.o., for five days. Tail flick latencies were noted on all days, 90 min after SAM administration. 2.7.2. Effect of combination of sub analgesic dose of morphine (3 mg/kg) and SAM (800 mg/kg) to rule out an additive effect Rats were divided into three groups and received vehicle, morphine in sub analgesic dose (3 mg/kg, i.p.) and combination of SAM (800 mg/kg) and sub analgesic dose of morphine daily for five days. Morphine was administered 45 min after SAM administration and TFLs were taken at 90 min after SAM administration. 2.8. Statistical analysis Fig. 5. Proposed transport mechanism of SAM into brain after oral administration in rats. A-Methyl transferases; B-SAM hydrolase; C-␥-cystathionase; D-methionine adenosyltransferase; E-Methionine synthases; SAH- S-adenosine homocysteine;SAM-S-adenosine methionine; GIT-Gastro intestinal tract.
The latencies were converted to percent maximal possible effect (% MPE), calculated as − %MPE =
baseline TFLs ≤ 8.0 s. Any animal showing baseline value greater than 8.0 s was not included. During experimentation, a cut-off time of double the baseline was used to avoid injury to the rats.
2.4. Determination of peak effect of SAM and morphine on analgesic activity using tail flick test in rats Rats were divided into three groups, vehicle control, SAM 400 and 800 mg/kg. SAM was administered orally by gavage, this being the intended route for clinical use and tail flick latencies were taken every 30 min upto 2 h. A single dose of SAM did not show any analgesic effect with any of the dose used (data not shown). However, 800 mg/kg on repetitive dosing exhibited an analgesic effect on day 5. Hence SAM 800 mg/kg was used for further experiments. In a separate group of rats, morphine at 7.0 mg/kg, i.p. was administered and tail flick latencies were taken every 15 min up to 2 h. The SAM peak was seen at 90 min while morphine effect peaked at 45 min (data not shown). For further experiments, TFLs were determined at 45 and 90 min after morphine and SAM administration respectively.
2.5. Development of morphine tolerance using tail flick test in rats Rats were divided into two groups and received vehicle or morphine at 7 mg/kg. Morphine was administered daily for five days followed by determination of TFL at 45 min, since the peak effect was at this time point.
(Post treatment latency-Pretreatment latency) × 100 Pretreatment latency
The analyses of data were performed by an observer naïve to study groups. Levene, s test was used to determine homogeneity of variances. Since all data was nonparametric, Mann Whitney, Kruskal Wallis and chi square tests were used. Dunn’s posthoc test was used to determine significance between groups. The ␣ level was set at 0.05. STATA 10 software was used for data analysis. In the figures, % MPE is plotted vs number of days as box plots. The box represents the interquartile range, the line within the box is the median. The ends of the ‘whiskers’ show maximum and minimum values. 3. Results The baseline tail flick latencies were not significantly different among different groups. 3.1. Development of tolerance with morphine Morphine at 7 mg/kg, i.p., showed the highest analgesic activity on day 1 (p-value = 0.0022, Mann-Whitney u = 0.0000; median = 100.0 vs control 7.58; minimum and maximum values 65.67 and 100.0 vs control −18.82 and 19.43 respectively) after which the analgesia declined. The median values for morphine being 39.63, 37.31, 0.27, 13.19 vs 15.10, −1.69, 6.93, 8.95 for control from days 2–5 respectively. TFLs for morphine and vehicle control were not significantly different at day 4 and 5 (p-value = 0.3939 and 0.8182; Mann-Whitney u = 12.00 and 16.00 on day 4 and 5 respectively) (Fig. 2).
2.6. Determination of effect of SAM co-administration with morphine on morphine tolerance using tail flick test in rats
3.2. Effect of SAM (800 mg/kg, po) and morphine (7 mg/kg, ip) co-administration on morphine tolerance
Rats were divided into four groups, vehicle control, SAM 800 mg/kg, morphine 7 mg/kg and their combination i.e. SAM 800 mg/kg + morphine 7 mg/kg. Morphine was administered after 45 min of SAM administration and TFL was taken after 90 min of SAM administration every day. This protocol was followed for 5 days (Refer Fig. 1).
Co-administering SAM at 800 mg/kg, p.o., 45 min before morphine administration reversed the morphine tolerance and a statistically significant analgesic effect was maintained on all days (Day 1–5) (p-values: 0.0001, 0.0017, 0.0002; 0.0001 and 0.0001; chi-sqr = 19.651, 18.883, 18.127, 17.033 and 18.313; d.f. = 3 from day 1–5 respectively) (Fig. 3).
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Fig. 6. Proposed mechanism of reversal of morphine tolerance. Chronic morphine administration blocks the influx of cysteine and alters the SAM levels and epigenetic expression, resulting in morphine tolerance. Exogenous SAM administration would replenish the SAM levels and therefore may reverse the morphine tolerance. SAM-Sadenosyl methionine; EAAT3-Excitatory amino acid transporter 3.
3.3. Effect of opioid receptor antagonist naloxone on analgesic effect of SAM Naloxone at 0.5 mg/kg, i.p., had no significant effect on TFLs but when naloxone was administered with SAM, it significantly antagonized the analgesic effect of SAM on TFLs (Fig. 4a) (NC vs SAM or SAM + NAL p-value = 0.0075 and 1.0000; chi-sqr = 12.69; d.f.=3; median, minimum and maximum values −8.988, −30.84 and 14.69 vs 33.37, 25.53 and 51.02 respectively). 3.4. Interaction of SAM (800 mg/kg, po) with sub analgesic dose of morphine (3 mg/kg, ip) Daily administration of morphine at sub analgesic dose (3 mg/kg, i.p.) showed no analgesic effect. Co-administration of SAM at 800 mg/kg, p.o., showed no additive effect on TFLs rather the analgesic effect of SAM was also not seen (Day 5, NC vs SAM or NC vs SAM + MOR3, p-value = 0.0112 and 0.8648 respectively; chi-sqr = 10.763; d.f. = 3) (Fig. 4b). 4. Discussion Tolerance to morphine is a major limitation in its use as an analgesic. This tolerance to morphine can develop even after a single dose [26]. In our study as well, antinociceptive activity of morphine declined from day 2 onwards. Multiple mechanisms and effectors have been implicated in opioid tolerance and dependence. Garzon et al. [27] suggest that in order to diminish tolerance it is crucial to identify additional links. S-adenosyl-l-methionine (SAM) is a nutraceutical, with clinically demonstrated efficacy and safety in osteoarthritis [28]. Mechanistically, SAM is involved in three major biochemical pathways −transsulfuration, aminopropylation and methylation, which, in turn can potentially modulate inflammatory mediators, proteoglycan synthesis, cell signalling, glutathione levels and DNA
methylation [29]. We evaluated usefulness of SAM in morphine tolerance using tail flick latency test in rats. Tail-flick in rodents involves a spinal nociceptive reflex and the reaction times are used for evaluating analgesic activity. The human equivalent dose of SAM (200 mg/kg), did not show any analgesic activity in pilot study therefore, higher doses of SAM, (400 and 800 mg/kg, p.o.) were also evaluated. A single dose of SAM did not show any analgesic effect at any of the dose used. However, 800 mg/kg on repetitive dosing exhibited an analgesic effect. The maximum analgesic activity of SAM was observed at 90 min which is in agreement with previous reports [23]. The efficacy after repeated daily dosing and with higher doses is likely due to the intricate feedback regulation of SAM levels in the body via the methionine cycle (Fig. 5). On exogenous administration, the excess SAM is converted to methionine which can cross the blood brain barrier freely unlike SAM which does so poorly. The methionine that crosses to brain could be contributing to the analgesic activity directly or via conversion to SAM within the brain. An analgesic activity with methionine has been reported [23]. However, time to peak analgesic activity (90 min) is more in line with the effect being due to SAM rather than methionine. The mechanism of analgesic activity of SAM has not been worked out. We evaluated the role of opioid receptors in the analgesic activity of SAM using naloxone an opioid receptor antagonist. Naloxone significantly attenuated the analgesic activity of SAM suggesting an interaction between SAM and opioidergic system. At the same time combination of low dose morphine and SAM 800 mg/kg did not show any additive effect rather, the effect of SAM was attenuated. Opposing effects of different doses of morphine with acute administration have been reported previously, [30,31], but these cannot explain our results as we have used a repeated dosing protocol. It is likely that SAM shows analgesia by facilitating endogenous opioids. Repeated administrations of morphine 3 mg/kg would results in downregulation of opioidergic receptors and therefore attenuated SAM analgesia. The combination of mor-
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phine 7 mg/kg with SAM could also have attenuated the analgesic effect of SAM but the attenuation of SAM analgesia was masked by analgesic effect due to reversal of morphine tolerance. It has been previously proposed that opioid-induced adaptations occur at different levels in the nervous system [27]. Recently, Trivedi and Deth [18] have proposed that morphine tolerance and addiction may be due to epigenetic changes which are mediated to some extent by change in methylation status. In their studies using neuronal cell culture, morphine via mu receptors inhibited excitatory amino acid transporter-3(EAAT-3), mediated cysteine uptake. The cysteine uptake has been associated with alterations in redox status, glutathione levels and DNA methylation [17]. As hypothesised, the exogenous SAM co-administration attenuated morphine tolerance (Refer Fig. 6).
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[5]
[6]
[7]
[8]
4.1. Limitations A limitation of this study could be high inter-animal variability with opioidergic interventions. Also, since the study was planned as a proof of concept in intact animal, simultaneous mechanistic/biochemical determinations have not been carried out. It is therefore not possible to exclude any off target effect of SAM given the high dose used or any other hitherto unknown effect for reversing morphine tolerance.
[9]
[10]
[11]
4.2. Conclusion and future directions These results have implication not only for preventing morphine tolerance but also SAM can be explored in drug addiction and withdrawal. Besides, a detailed study of locus and biochemical mechanisms involved at molecular level can also yield valuable information and further targets. Conflict of interest statement The authors declare no conflicts of interest.
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[13]
[14]
[15] [16]
Authors contribution Jatinder Katyal: Substantial contribution to concept, design, interpretation of data, drafting, revision and final approval of the manuscript. Hemant Kumar: Substantial contribution to concept, design, acquisition, analysis, drafting, revision and interpretation of data, and final approval of the manuscript. Dinesh Joshi: Substantial contribution to design and acquisition of data and final approval of the manuscript. Yogendra Kumar Gupta: Substantial contribution to concept, interpretation of data, drafting, revision and final approval of the manuscript.
[17]
[18]
[19]
[20] [21]
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.neulet.2017.02. 054.
[22]
References
[24]
[1] J.T. Williams, S.L. Ingram, G. Henderson, C. Chavkin, M. von Zastrow, S. Schulz, T. Koch, C.J. Evans, M.J. Christie, Regulation of -opioid receptors: desensitization, phosphorylation, internalization, and tolerance, Pharmacol. Rev. 15 (2013) 223–254, http://dx.doi.org/10.1124/pr.112.005942. [2] B.L. Kieffer, C.J. Evans, Opioid tolerance-in search of the holy grail, Cell 8 (2002) 587–590, http://dx.doi.org/10.1016/s0092-8674(02)00666-9. [3] S.L. Mercer, A. Coop, Opioid analgesics and P-glycoprotein efflux transporters: a potential systems-level contribution to analgesic tolerance, Curr. Top. Med.
[23]
[25]
[26]
Chem. 11 (2011) 1157–1164, http://dx.doi.org/10.2174/ 156802611795371288. ˜ M. Rodríguez-Munoz, J. Garzón, Nitric oxide and zinc-mediated protein assemblies involved in mu opioid receptor signalling, Mol. Neurobiol. 48 (2013) 769–782, http://dx.doi.org/10.1007/s12035-013-8465-z. E. Erami, H. Azhdari-Zarmehri, A. Rahmani, E. Ghasemi-Dashkhasan, S. Semnanian, A. Haghparast, Blockade of orexin receptor 1 attenuates the development of morphine tolerance and physical dependence in rats, Pharmacol. Biochem. Behav. 103 (2012) 212–219, http://dx.doi.org/10.1016/j. pbb.2012.08.010. L.N. Eidson, A.S. Murphy, Blockade of toll-like receptor 4 attenuates morphine tolerance and facilitates the pain relieving properties of morphine, J. Neurosci. 33 (2013) 15952–15963. ˜ P. Sánchez-Blázquez, M. Rodríguez-Munoz, E. Berrocoso, J. Garzón, The plasticity of the association between mu-opioid receptor and glutamate ionotropic receptor N in opioid analgesic tolerance and neuropathic pain, Eur. J. Pharmacol. 716 (2013) 94–105, http://dx.doi.org/10.1016/j.ejphar.2013.01. 066. L.M. Bohn, R.R. Gainetdinov, F. Lin, R.J. Lefkowitz, M.G. Caron, Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence, Nature 408 (2000) 720–723, http://dx.doi.org/10.1038/ 35047086. K. Nakamoto, S. Kawasaki, T. Kobori, W. Fujita-Hamabe, H. Mizoguchi, K. Yamada, T. Nabeshima, S. Tokuyama, Involvement of matrix metalloproteinase-9 in the development of morphine tolerance, Eur. J. Pharmacol. 683 (2012) 86–92, http://dx.doi.org/10.1016/j.ejphar.2012.03.006. J.W. Little, S. Cuzzocrea, L. Bryant, E. Esposito, T. Doyle, S. Rausaria, W.L. Neumann, D. Salvemini, Spinal mitochondrial-derived peroxynitrite enhances neuroimmune activation during morphine hyperalgesia and antinociceptive tolerance, Pain 154 (2013) 978–986, http://dx.doi.org/10.1016/j.pain.2013.02. 018. H. Ghavimi, M. Charkhpour, S. Ghasemi, M. Mesgari, H. Hamishehkar, K. Hassanzadeh, S. Arami, K. Hassanzadeh, Pioglitazone prevents morphine antinociceptive tolerance via ameliorating neuroinflammation in rat cerebral cortex, Pharmacol. Rep. 67 (2015) 78–84, http://dx.doi.org/10.1016/j.pharep. 2014.08.003. G. Jun, S.H. Kim, Y.I. Yoon, J.Y. Park, Intrathecal lamotrigine attenuates antinociceptive morphine tolerance and suppresses spinal glial cell activation in morphine-tolerant rats, J. Korean Med. Sci. 28 (2013) 300–307, http://dx. doi.org/10.3346/jkms.2013.28.2.300. C. Yang, Y. Chen, L. Tang, Z.J. Wang, Haloperidol disrupts opioid-antinociceptive tolerance and physical dependence, J. Pharmacol. Exp. Ther. 338 (2011) 164–172, http://dx.doi.org/10.1124/jpet.110.175539. L. Tang, P.K. Shukla, Z.J. Wang, Trifluoperazine, an orally available clinically used drug, disrupts opioid antinociceptive tolerance, Neurosci. Lett. 397 (2006) 1–4, http://dx.doi.org/10.1016/j.neulet.2005.11.050. M.S. Trivedi, N.W. Hodgson, J.S. Shah, R.C. Deth, A novel redox based epigenetic signalling mechanism for opioids, FASEB J. 27 (2013) 1180–1188. M.S. Trivedi, J.S. Shah, N.W. Hodgson, H.M. Byun, R.C. Deth, Morphine induced redox based changes in global DNA methylation and retrotransposon transcription by inhibition of excitatory amino acid transporter type 3-mediated cysteine uptake, Mol. Pharmacol. 85 (2014) 747–757, http://dx. doi.org/10.1124/mol.114.091728. M.S. Trivedi, J.S. Shah, S. Al-Mughairy, N.W. Hogdson, B. Simms, G.A. Troosken, W.V. Creikinge, R.C. Deth, Food derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences, J. Nutr. Biochem. 25 (2014) 1011–1018, http://dx.doi.org/10.1016/j.jnutbio.2014.05.004. M.S. Trivedi, R.C. Deth, Redox based epigenetic status in drug addiction: a potential contributor to gene priming and a mechanistic rationale for metabolic intervention, Front. Neurosci. 8 (2015) 1–13, http://dx.doi.org/10. 3389/fnins.2014.00444. P.K. Chiang, R.K. Gordon, J. Tal, G.C. Zeng, B.P. Doctor, K. Pardhasaradhi, P.P. McCann, S-Adenosyl methionine and methylation, FASEB J. 10 (1996) 471–480. J.M. Mato, S.C. Lu, Role of S-adenosyl-L-methionine in liver health and injury, Hepatology 45 (2007) 1306–1312, http://dx.doi.org/10.1002/hep.21650. W.I. Najm, S. Reinsch, F. Hoehler, J.S. Tobis, P.W. Harvey, S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial, BMC Musculoskelet Disord. 26 (2004) 5–6, http://dx.doi.org/10.1186/ISRCTN36233495. D. Mischoulon, M. Fava, Role of S-adenosyl methionine in the treatment of depression: a review of the evidence, Am. J. Clin. Nutr. 76 (2002) 1158S–1161S. S.N. Young, M. Shalchi, The effect of methionine and S-Adenosylmethionine on S-adenosylmethionine levels in the rat brain, Rev. Psychiatr. Neurosci. 30 (2005) 44–48. J. Katyal, Y.K. Gupta, Dopamine release is involved in antinociceptive effect of theophylline, Int. J. Neurosci. 122 (2012) 17–21, http://dx.doi.org/10.3109/ 00207454.2011.613550. J. Malhotra, G. Chaudhary, Y.K. Gupta, Dopaminergic involvement in adenosine A1 receptor mediated antinociception in tail flick latency model in mice, Methods Find. Exp. Clin. Pharmacol. 22 (2000) 37–41, http://dx.doi.org/ 10.1358/mf.2000.22.1.795826. F. Ferrini, T. Trang, T.A. Mattioli, S. Laffray, T. Del’Guidice, L. Lorenzo, A. Castonguay, N. Doyon, W. Zhang, A. Godin, D. Mohr, S. Beggs, K. Vandal, J. Beaulieu, C.C. Cahill, M.W. Salter, Y.D. Koninch, Morphine hyperalgesia gated
J. Katyal et al. / Neuroscience Letters 645 (2017) 67–73 through microglia mediated disruption of Cl− homeostasis, Nat. Neurosci. 16 (2013) 182–193, http://dx.doi.org/10.1038/nn.3295. ˜ P. Sánchez-Blázquez, Do pharmacological [27] J. Garzón, M. Rodríguez-Munoz, approaches that prevent opioid tolerance target different elements in the same regulatory machinery, Curr. Drug Abuse Rev. 1 (2008) 222–238. [28] De Silva, A. El-Metwally, E. Ernst, G. Lewith, G.J. Macfarlane, Evidence for the efficacy of complementary and alternative medicines in the management of osteoarthritis: a systematic review, Rheumatology 50 (2011) 911–920, http:// dx.doi.org/10.1093/rheumatology/keq379.
73
[29] H.J. Blewett, Exploring the mechanisms behind S- adenosylmethionine (SAMe) in the treatment of osteoarthritis, Crit. Rev. Food Sci. Nutr. 48 (2008) 458–463, http://dx.doi.org/10.1080/10408390701429526. [30] Y.K. Gupta, A. Chugh, S.D. Seth, Opposing effect of apomorphine on antinociceptive activity of morphine: a dose-dependent phenomenon, Pain 36 (1989) 263–269, http://dx.doi.org/10.1016/0304-3959(89)90032-8. [31] M.R. Zarrindast, E. Moghaddampour, Opposing influences of D-1 and D-2 dopamine receptors activation on morphine-induced antinociception, Arch. Int. Pharmacodyn. Ther. 300 (1989) 37–50.