European Journal of Pharmacology 761 (2015) 268–272
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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Neuropharmacology and analgesia
Tianeptine prevents respiratory depression without affecting analgesic effect of opiates in conscious rats David Cavalla a,b, Fabio Chianelli b, Alla Korsak c, Patrick S. Hosford c, Alexander V. Gourine c,1, Nephtali Marina d,n,1 a
Numedicus Limited, Cambridge CB1 2DX, United Kingdom Revive Therapeutics Ltd., 5 Director Court, Suite 105, Vaughan, Ontario L4L 4S5, Canada c Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom d UCL Department of Clinical Pharmacology, University College London, London WC1E 6JF, United Kingdom b
art ic l e i nf o
a b s t r a c t
Article history: Received 15 January 2015 Received in revised form 21 April 2015 Accepted 18 May 2015 Available online 8 June 2015
Respiratory depression remains an important clinical problem that limits the use of opiate analgesia. Activation of AMPA glutamate receptors has been shown to reverse fentanyl-induced respiratory changes. Here, we explored whether tianeptine, a drug known for its ability to phosphorylate AMPA receptors, can be used to prevent opiate-induced respiratory depression. A model of respiratory depression in conscious rats was produced by administration of morphine (10 mg/kg, i.p.). Rats were pre-treated with test compounds or control solutions 5 min prior to administration of morphine. Respiratory activity was measured using whole-body plethysmography. In conscious animals, tianeptine (2 and 10 mg/kg, ip) and DP-201 (2-(4-((3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2] thiazepin-11-yl)amino)butoxy)acetic acid; tianeptine analogue; 2 mg/kg, ip) triggered significant ( 30%) increases in baseline respiratory activity and prevented morphine-induced respiratory depression. These effects were similar to those produced by an ampakine CX-546 (15 mg/kg, ip). The antinociceptive effect of morphine (hot plate test) was unaffected by tianeptine pre-treatment. In conclusion, the results of the experiments conducted in conscious rats demonstrate that systemic administration of tianeptine increases respiratory output and prevents morphine-induced respiratory depression without interfering with the antinociceptive effect of opiates. & 2015 Elsevier B.V. All rights reserved.
Keywords: Ampakines Analgesia Morphine Nociception Opiates Respiratory depression Tianeptine
1. Introduction Opiates are the most commonly prescribed agents for the relief of postoperative pain. Of all their unwanted side effects, respiratory depression is of a greatest concern. The ability of opiates to reduce respiratory rate and tidal volume, as well as respiratory sensitivity to CO2 has been long known (Shook et al., 1990). Opiate-induced respiratory depression is a life-threatening condition and a leading cause of death that may arise not only from overdose, but also during routine procedures supervised by clinicians, including surgical anaesthesia, post-operative analgesia, and as a result of routine out-patient management of pain from cancer, accidents, or other illnesses (Dahan et al., 2010). Although only 0.5–1.2% of all adverse drug effects caused by n
Corresponding author. E-mail addresses:
[email protected] (D. Cavalla),
[email protected] (F. Chianelli),
[email protected] (A. Korsak),
[email protected] (A.V. Gourine),
[email protected] (N. Marina). 1 joint last authors. http://dx.doi.org/10.1016/j.ejphar.2015.05.067 0014-2999/& 2015 Elsevier B.V. All rights reserved.
prescription medications are respiratory in nature, these are serious and much more common in the context of patient controlled analgesia (Overdyk et al., 2007). Certain conditions predispose to respiratory depression such as morbid obesity, sleep apnoea, severe pain (patients receiving high doses of opiates) and chronic lung disease. Up to 35% of all surgical patients fall into these high-risk categories. Central respiratory drive is generated by bilaterally organised groups of respiratory neurones located in the ventrolateral regions of the medulla oblongata (Richter and Spyer, 2001; Feldman and Del Negro, 2006). Medullary respiratory network has been identified as being responsible for the decrease in the respiratory output following systemic administration of opiates (Ren et al., 2006). In addition, opiates suppress the activity of hypoglossal (XII) motoneurones which innervate tongue muscles and are vital for maintaining upper-airway patency. In emergency situations, administration of μopioid receptor antagonists such as naloxone is highly effective, but it also takes the patient out of analgesia. Therefore, development or identification of novel compounds that prevent respiratory depression associated with opiate analgesia without interfering with their
D. Cavalla et al. / European Journal of Pharmacology 761 (2015) 268–272
analgesic effects is an important task. The α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) glutamate receptors mediate excitatory inputs to XII motoneurones. Positive allosteric modulation of AMPA receptors by a group of compounds called AMPAkines (such as CX717 and others) has been shown to block as well as reverse respiratory depression induced by fentanyl in animal models and human volunteers (Oertel et al., 2010). Tianeptine is a singular antidepressant that is proposed to be a “neuroplasticity enhancer” (Kole et al., 2002; McEwen et al., 2009; Szegedi et al., 2011). The exact underlying molecular mechanisms of its action remains unknown, but it has been shown that tianeptine increases the rate of phosphorylation at both the Ser831 and Ser845 residues of GluA1 subunit of AMPA receptors (Svenningsson et al., 2007; Qi et al., 2009; Barkóczi et al., 2012). There is evidence that tianeptine enhances the amplitude of the excitatory post-synaptic potentials (fEPSPs) in murine hippocampal slices – the effect which was blocked by kinase inhibitors (Zhang et al., 2013). High efficacy of AMPAkines in reducing opiate-induced respiratory depression suggested that the agents with a similar pharmacological profile may have a similar effect. Since tianeptine is capable of facilitating AMPA-mediated glutamatergic transmission we tested the effect of this compound on opiate-induced respiratory depression in an animal model.
2. Materials and methods Experiments were performed in accordance with the European Commission Directive 86/609/EEC (European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes) and the UK Home Office (Scientific Procedures) Act (1986) with project approval from the respective Institutional Animal Care and Use Committees. 2.1. Experimental animals A total of 82 male Sprague-Dawley rats (200–250 g body weight) were used in this study. Animals were fed ad libitum with a commercial rodent feed and had free access to drinking water. Animals were kept in automatically controlled environmental conditions set to maintain temperature at 22–24 °C with a relative humidity of 30–70%, and a 12:12 h light:dark cycle. At the end of the experiments the animals were humanely euthanized by an overdose of anaesthetic (pentobarbitone sodium, 200 mg/kg, ip).
269
rate (fR, in breaths per minute), tidal volume (VT, in microlitres per gram of body weight) and minute ventilation (VE ¼fR VT) in conscious rats as described (Trapp et al., 2008, 2011). Briefly, the animals were placed in a recording chamber (∼700 ml) flushed continuously with a humidified mixture of 79% nitrogen and 21% oxygen (temperature 22–24 °C). Level of CO2 in the chamber was monitored online using a fast-response CO2 analyser (Capstar 100, CWE). The animals were allowed ∼40 min to acclimatize to the chamber environment (21% O2, 79% N2 and o 0.3% CO2) before measurements of baseline ventilation were taken. 2.3. Model of opiate-induced respiratory depression Respiratory depression in conscious rats was induced by intramuscular (10 mg/kg) administration of morphine (May and Baker). Prior to morphine administration, animals were randomly assigned to the experimental groups and received an intraperitoneal injection of either saline solution (control), tianeptine (2 mg/kg or 10 mg/kg, Kemprotec Ltd.), AMPAkine CX-546 (15 mg/kg, Tocris) or tianeptine analogue DP-201 (2 mg/kg, Peakdale Molecular Limited) (Table 1). 2.4. Assessment of the nociceptive threshold Rats were injected with saline (ip) or tianeptine (10 mg/kg, ip) followed in 30 min by administration of morphine (10 mg/kg, im). Animals were then placed one at a time on a hot plate (52.5 °C) at intervals of 30, 90 and 240 min after morphine administration. Latency to respond to the heat stimulus was measured by the amount of time it took the animal to lick one of its rear paws or until cut-off time was reached (90 s). 2.5. Data acquisition and analysis The data were acquired using Power1401 interface (CED Ltd., Cambridge, UK), saved and analysed off-line using Spike2 software (CED). Data are presented as means7SEM. Group data were compared by two-way ANOVA with repeated measures followed by Bonferroni's post-hoc analysis or one-way ANOVA followed by Tukey–Kramer's post-hoc analysis, as appropriate. Differences between the experimental groups with Po0.05 were considered significant.
3. Results 3.1. The effect of tianeptine on the respiratory activity and opiateinduced respiratory depression in rats
2.2. Assessment of the respiratory activity Whole-body plethysmography was used to measure respiratory
In conscious rats, systemic administration of tianeptine (2 mg/ kg, ip) increased the respiratory activity (by 30%) 5 min after the
Table 1 Summary of the experimental groups. Experiment
n
Test material
Anaesthesia
Route
Dose
RD RD RD RD RD NT NT NT NT NT NT
20 10 10 4 6 5 5 5 5 7 5
Saline Tianeptine Tianeptine CX546 DP-201
Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious
ip ip ip ip ip
2 mg/kg 10 mg/kg 15 mg/kg 2 mg/kg
Saline Tianeptine Saline Tianeptine
RD – Respiratory depression, NT – Nociceptive threshold, ip – intraperitoneal, im – intramuscular.
ip ip ip ip
10 mg/kg 10 mg/kg
Treatment Morphine, 10 mg/kg, im Morphine, 10 mg/kg, im Morphine, 10 mg/kg, im Morphine, 10 mg/kg, im Morphine, 10 mg/kg, im Saline, im Morphine, 10 mg/kg, im Morphine, 10 mg/kg, im Morphine, 10 mg/kg, im Morphine, 5 mg/kg, im Morphine, 5 mg/kg, im
D. Cavalla et al. / European Journal of Pharmacology 761 (2015) 268–272
30
Saline + morphine (n=20) Tianeptine, 2mg kg -1 + morphine (n=10) Tianeptine, 10mg kg -1 + morphine (n=10)
Δ RR (%)
15
*
30
Saline + morphine (n=20) CX546, 15mg kg -1 + morphine (n=4)
15
Δ RR (%)
injections (n ¼10, Fig 1). In control animals (saline i.p) administration of morphine (10 mg/kg) led to a significant respiratory depression as evident from a reduction of minute ventilation by 30% (n ¼ 20, Fig. 1). In rats pre-treated with tianeptine (2 mg/kg), morphine actions were not associated with decreases in ventilation below the baseline (n ¼10, Fig. 1), demonstrating that tianeptine effectively prevented opiate-induced respiratory depression. An increase in the respiratory activity shortly after the injections was not observed in rats injected with tianeptine at a dose of 10 mg/kg, however morphine-induced respiratory depression was similarly prevented (n ¼10, Fig. 1). The effect of tianeptine on resting respiratory activity and morphine-induced respiratory depression in conscious rats was similar to that produced by an AMPAkine CX-546 (15 mg/kg, ip) (n ¼ 4, Fig. 2). In conscious rats, DP-201 (tianeptine analogue; 2 mg/kg, ip) induced a significant increase in the respiratory activity 5 min after administration and prevented morphine-induced respiratory depression (n¼ 6, Fig. 3).
* 0
-15
-30
*
75 50
Δ VT (%)
270
#
*
25
*
0 -25
0
-50 -15
100
*
-30
* #
Δ VT (%)
25
*
#
*
0
-25
50
* *
0
-50 Before CX546
-50 100
* Δ VE (%)
Δ VE (%)
50
50 #
* 0
#
*
0 30 60 Time after morphine injection (min)
Fig. 2. The effect of AMPAkine CX-546 (15 mg/kg) on morphine-induced respiratory depression in conscious rats. Summary data showing changes in the respiratory rate, tidal volume and minute ventilation induced by successive injections of CX-546 (15 mg/kg, ip) and morphine (10 mg/kg, im) in conscious rats. Two way ANOVA with repeated measures showed both main factors of time and drug treatment, respectively, were a significant source of variation for VT [P o0.0001 (F(3,66) ¼ 38.75), P¼ 0.0005 (F(1,22) ¼ 16.73)] and VE [Po 0.0001 (F¼ 57.75), P¼ 0.0004 (F ¼17.73)]. RR showed only time as a significant source of variation P o0.0001 (F(3,66) ¼ 12.18). Bonferonni post-hoc analysis was used to compare control and CX546 groups; *Po 0.05.
3.2. The effect of tianeptine on morphine-induced analgesia -50 Before Tianeptine
0
30
60
Time after morphine injection (min)
Fig. 1. The effect of tianeptine (2 and 10 mg/kg) on morphine-induced respiratory depression in conscious rats. Summary data showing changes in the respiratory rate (RR), tidal volume (VT) and minute ventilation (VE) induced by successive injections of tianeptine (2 and 10 mg/kg, ip) and morphine (10 mg/kg, im) in conscious rats. Two-way ANOVA with repeated measures showed both main factors of time and drug treatment, respectively, were a significant source of variation for RR [P o0.0001 (F(3,111) ¼ 19.51), P¼ 0.03 (F(2,37) ¼3.97)], VT [P o0.0001 (F ¼26.24), Po 0.0001 (F¼ 13.41)] and VE [Po 0.0001 (F¼ 49.63), P o0.0001 (F ¼12.40)]. Bonferonni post-hoc analysis was used to compare control and tianeptine-injected subjects; *Po 0.05; 2 mg/kg dose vs. control, #Po 0.05; 10 mg/kg dose vs. control.
In control animals, rear paw licking response to acute nociceptive stimulation measured 30, 90 and 240 min after intramuscular saline administration occurred after 34715, 2374 and 2573 s, respectively (n¼ 5, Table 2). Animals treated with morphine (10 mg/kg, im, n¼5) failed to show nociceptive responses 30 and 90 min after administration and were removed from the hot plate after cut-off time (90 s) had been reached. Similar level of antinociception was observed in response to morphine (10 mg/kg, im, n¼5) in animals treated with saline or tianeptine (10 mg/kg ip, n¼5 each, Table 2). In animals administered with lower dose of morphine (5 mg/kg im, n¼7), the latencies of responses to acute
D. Cavalla et al. / European Journal of Pharmacology 761 (2015) 268–272
30 Saline + morphine (n=20) DP-201 2mg kg -1 + morphine (n=6)
Δ RR (%)
15
* 0
-30 75
*
50
Δ VT (%)
Table 2 The anti-nociceptive effect of morphine is unaffected by tianeptine. Rear paw licking time was determined 30, 90 and 240 min after morphine administration. Animals were removed from the hot plate immediately after the licking response or after cut-off time had been reached (90 s). One way ANOVA followed by the Tukey– Kramer's post-hoc test. n Treatment
-15
25
*
0
*
5 Saline i.m. 5 Morphine (10 mg/kg, im) 5 Saline i.p. þmorphine (10 mg/kg, im) 5 Tianeptine (10 mg/kg) þmorphine (10 mg/kg, im) 7 Saline i.p. þmorphine (5 mg/kg, im) 5 Tianeptine (10 mg/kg) þmorphine (5 mg/kg, im) n
-25 -50 100
Δ VE (%)
* 50
* 0
*
-50
Before DP-201
0 30 60 Time after morphine injection (min)
Fig. 3. The effect of tianeptine analogue DP-201 (2 mg/kg) on morphine-induced respiratory depression in conscious rats. Summary data showing changes in the respiratory rate, tidal volume and minute ventilation induced by successive injections of DP-201 (2 mg/kg, ip) and morphine (10 mg/kg, im) in conscious rats. Two way ANOVA with repeated measures showed both main factors of time and drug treatment, respectively, were a significant source of variation for RR [Po 0.0001 (F(3,72) ¼ 17.20), P¼ 0.02 (F(1,24) ¼6.78)], VT [P o 0.0001 (F ¼55.87), P¼ 0.0004 (F¼ 16.73)] and VE [p o 0.0001 (F¼ 76.75), P¼ 0.0003 (F¼ 18.35)]. Bonferonni posthoc analysis was used to compare control and D-201 groups; *P o 0.05.
nociceptive stimulation were significantly increased 30 and 90 min after the injections (8576 and 42712 s, respectively, both po0.05, Table 2) and these latencies were not different to those recorded in rats pretreated with tianeptine (10 mg/kg ip, n¼5) (8776 and 59731 s, respectively, Table 2).
271
Rear paw licking latency (s) 30′ after morphine 347 15 Cut-off
90′ after morphine 237 4 Cut-off
240′ after morphine 25 73 43 718n
Cut-off
Cut-off
517 7n
Cut-off
Cut-off
487 11n
857 6n
427 12n
20 78
877 6n
597 31n
26.8 7 11n
p o 0.05 compared to saline-treated group (group 1).
lateral amygdala (Pillai et al., 2012). Of all anti-depressants used, it possesses the safest therapeutic window, with patients being able to significantly overdose the drug without adverse consequences (Wilde and Benfield, 1995). Moreover, the concern that facilitated AMPA-mediated signalling can predispose patients to epileptic seizures (Rogawski and Donevan, 1999) seems not to be a problem with tianeptine (Baudry et al., 2012; Moon et al., 2014). Various mechanisms underlying the mode of action of tianeptine have been proposed, including stimulation of 5-HT uptake in the cortex and hippocampus (Mocaër et al., 1988), the effects in the lung through modulation of 5-HT3 and 5-HT4 receptors (Lechin et al., 2004) and via the actions on hippocampal nitric oxidemediated signalling (Wegener et al., 2003). Tianeptine has also been shown to activate Calcium–Calmodulin-dependant protein kinase II (CaMKII) and protein kinase A (PKA) via the p38, p42/44 Mitogen-activated protein kinases (MAPK) and c-Jun N-terminal kinases (JNK) pathways in the hypothalamus and cortex (Szegedi et al., 2011). However, an extensive binding study of 5-HT receptors, dopamine receptors, adrenoceptors, glutamate receptors and various transporters revealed that tianeptine has no significant affinity for any of these potential targets (Svenningsson et al., 2007). Our experiments demonstrated that tianeptine does not reduce the efficacy of morphine-induced antinociception. This observation is not surprising since tianeptine itself has been shown to display some anti-nociceptive properties when applied intrathecally in an animal pain model produced by intra-plantar formalin administration (Kim et al., 2012). More recent evidence suggests that tianeptine may possesses some μ-opioid and, to a lesser extent, δ-opioid agonist activity (Gassaway et al., 2014). Muopioid agonists uniformly elicit, rather than oppose, respiratory depression and our data imply that positive AMPA receptor modulation by tianeptine overwhelm any μ-opioid agonist activity in regard to the control of the respiratory activity.
4. Discussion 5. Conclusions Results obtained in the present study demonstrate that in conscious rats, tianeptine administered systemically increases the respiratory output and prevents morphine-induced respiratory depression without affecting opiate-induced analgesia. Tianeptine possesses a unique pharmacological profile which includes positive modulation of AMPA-mediated transmission in the hippocampus and negative modulation of NMDA-mediated signalling in the
These results suggest that tianeptine can be potentially used to prevent unwanted side effects associated with opiate therapy, including respiratory depression. Antinociceptive properties of tianeptine along with its proved efficacy and tolerability make this compound a potential coadjuvant in combination with opiates for the management of pain.
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Acknowledgements This study was funded by Revive Therapeutics Ltd (REV-UCL001). Revive Therapeutics Ltd. is developing tianeptine for the treatment of respiratory depression. D.C. is an inventor of the technology comprising the use of tianeptine for the treatment of respiratory depression and a consultant to Revive Therapeutics Ltd. F.C. is the Founder, Chief Executive Officer and Director of Revive Therapeutics Ltd. A.V.G. is a consultant to Revive Therapeutics Ltd.
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