Opiates are analgesic agents and commonly prescribed for the relief of postoperative pain. However the unwanted effects of opiates include respiratory depression which is a concern to physicians. The ability of opiates to reduce respiratory rate, tidal volume and respiratory sensitivity to CO2 has long been known and can be life threatening (3). Central respiratory drive is generated by respiratory neurons in the ventral region of medulla oblongata (specifically RVLM neurons) and has been shown to be responsible for the decrease in the respiratory output following systemic administration of opiates (4). In an emergency, administration of µ-opiate receptor antagonists such as naloxone is highly effective for reversing the respiratory depression. However administration of naloxone also takes the patient out of analgesia. Therefore development of novel compounds that prevent respiratory depression associated with opiate analgesia without interfering with their analgesic effects is important for postoperative depression.
What are AMPAkines?
AMPAkines are positive allosteric modulators (PAMs) for the treatment for respiratory depression.
- Glutamate is the major excitatory neurotransmitter in the CNS and fast excitatory transmission is mediated by AMPA-type glutamate receptors
- AMPAkines are positive allosteric modulators of the AMPA-type glutamate receptor. AMPAkines prolong and strengthen synaptic transmission
- Neurons in this brainstem region (RVLM) control in respiratory breathing rhythm and use AMPA receptors for signaling (4).
- Opiates mediate their inhibitory effects on breathing at this brain region (RVLM) and AMPA-PAMs normalize breathing by enhancing firing of RVLM respiratory rhythm neurons.
What is Tianeptine?
Tianeptine, is a new class of antidepressant agent which increases the serotonin uptake in the brain and reduces stress-induced atrophy of neuronal dendrites without the side effects associated with SSRI (2). As well acting on serotonergic system tianeptine also shown to act on other neuronal pathways. A study by Kole at al shown that tianeptine enhanced, or prolong, synaptic plasticity and suggested that this actions are modulating the glutamate receptors in the CA3 region of the hippocampus (it modulate glutamate receptors by stabilising NMDA receptor to AMPA/kainate receptor-mediated currents (6). Study by Zhang et al shown that tianeptine enhanced the amplitude of excitatory post synaptic potentials (EPSPs) in murine hippocampal slices, an effect which is blocked by kinase inhibitors (5). However the exact mechanism of action is still unclear.
The ability of tianeptine to facilitate AMPA-mediated glutamatergic transmission is shown in a recent publication by Cavalla et al. The authors have tested the effects of tianeptine compounds on opiate-induced respiratory depression in a conscious rat animal model. The study has demonstrated that in conscious rats, when tianeptine is administered systemically, it increases the respiratory output and prevents morphine-induced respiratory depression without effecting opiate induced analgesia. They also tested CX-546 (an AMPAkine) on morphine-induced respiratory depression on the same model, showing that upregulation in the respiratory rate, tidal volume and minute ventilation are induced by successive injection of CX546 and morphine in conscious rats. There are concerns that up-regulated AMPA-mediated signaling can potentially induce patients to epileptic seizures, but seizures were not observed in this study (1).
This study provides encouraging evidence that Tianeptine can counter and reduce respiratory depression without interfering with analgesia. Development of therapeutic agents in this area will bring great clinical benefit.
Blog written by Hedaythul Choudhury
- Cavalla D, Chianelli F, Korsak A, Hosford PS, Gourine AV, Marina N. (2015) Tianeptine prevents respiratory depression without affecting analgesic effect of opiates in conscious rats. EJP 761 (2015) 268-272
- Wagstaff AJ, Ormrod D, Spencer CM. (2001) Tianeptine: a review of its use in depressive disorders. CNS Drugs. 2001; 15 (3):231-59.
- Shook JE1, Watkins WD, Camporesi EM. (1990) Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression. Am Rev Respir Dis. 1990 Oct; 142(4):895-909.
- Richter DW, Spyer KM. (2001) Studying rhythmogenesis of breathing: comparison of in vivo and in vitro models. Trends Neurosci. 2001 Aug; 24(8):464-72.
- Zhang H, Etherington LA, Hafner AS, Belelli D, Coussen F, Delagrange P, Chaouloff F, Spedding M, Lambert JJ, Choquet D, Groc L. (2013) Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule. Mol Psychiatry. 2013 Apr; 18(4):471-84. doi: 10.1038/mp.2012.80. Epub 2012 Jun 26.
- Kole MH, Swan L, Fuchs E. (2002) The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats. Eur J Neurosci. 2002 Sep; 16 (5):807-16.