Opioids in Depression: Not Quite There Yet

Xin Yin, Nuri Guven, Nikolas Dietis*

Division of Pharmacy, School of Medicine, University of Tasmania, Hobart 7001, Australia

Received: 02-Nov-2014 , Accepted: 27-Feb-2015

Keywords: Opioids, Morphine, Depression, Monoamines, Serotonin, Antidepressants

DOI: http://dx.doi.org/10.20510/ukjpb/3/i1/89219

Full-Text PDF      

XML                    

Google Scholar  

How To Cite       

Abstract

Depression is a common mental disorder that affects people of all ages across the world. All current pharmacological interventions are based on the monoamine theory of depression and aim to increase the concentrations of monoamines in the brain. However, since many patients show no response or do not tolerate conventional therapies, there is an urgent need to identify new therapeutic targets, explore new molecular pathways and develop novel drugs against depression. Opioids, a class of compounds used against chronic pain, have major analgesic properties, but they are also well known for their anxiolytic and antidepressant effects. In preclinical and clinical studies, some opioids showed encouraging results to alleviate depression-like symptoms. Although our knowledge about the antidepressant effects of opioids stretches back to the late ‘70s, we still have a long way to cover. Predominantly, a clear understanding about their mode of action as well as the opioid-associated issues of addiction and convulsions, are the main challenges that need to be addressed before we will see opioid compound used in the clinic against depression.

1 Opioids and pain: an established relationship

Pain is a symptom associated with a number of conditions and diseases such as cancer  or neuropathies, which remain a global public health concern due to the high percentage of documented undertreatment1-4. There are three types of pain; a classification that has been endorsed by the International Association for the Study of Pain (IASP): nociceptive pain, which is the stimulation of peripheral nerve fibres in response to noxious stimuli5, neuropathic pain, which is based on neuronal damage or misfiring of peripheral or central nervous system due to toxins, metabolic disturbances or virus infection among other reasons6, and combinatory pain that has both a nociceptive and neuropathic component, such as cancer pain7. Opioids are strong analgesics and the main drugs of choice in the treatment of moderate to severe acute pain, chronic pain and post-operative pain. These drugs essentially mimic the opiate action of endogenous ligands such as endomorphins, enkephalins and dynorphins, which activate the three classical Gi/o-coupled opioid receptors; mu- (MOP), delta- (DOP), kappa- (KOP)8. Basic classification, distribution, function, and pharmacology are summarized in Table 1. Although DOP and KOP receptor opioid binding plays a role in the modulation of pain signals, the MOP receptor is the major opioid receptor responsible for the analgesic effect of opioids, since MOP knock-out animals show abolished opioid-mediated analgesia9. A fourth receptor has been identified to exhibit a high degree of structural homology with the three opioid receptors, called nociceptin receptor (or NOP)10, but has been characterised by the International Union of Basic and Clinical Pharmacology (IUPHAR) as an “opioid-like” receptor and not an actual opioid receptor, due to its distinct pharmacology and its irrelevance with analgesia.

Even though the MOP receptors are mostly found in the central nervous system (spinal cord dorsal horn, thalamus, cortex, midbrain)11 where they inhibit nociceptive signals by intercepting ascending excitatory pathways and modulating the firing of GABAergic, serotonergic and dopanimergic neurons12, the non-analgesic effects of opioids are very well documented in the literature13. Opioid receptors are found in peripheral tissues where MOP-ligand binding is responsible for a number of peripheral effects such as respiratory depression, constipation and immunodepression 14. In addition, a number of behavioural non-analgesic opioid effects have also been documented in the literature.  Long-term morphine treatment is associated with alternations of cellular signalling in the reward centres that contribute to addiction and mood impairment15. MOP receptor desensitization has been shown to contribute to the development of physical dependence as a consequence of modulating inwardly rectifying K+ conductance at a cellular level16,17.

Gene knockout technology has provided consistent evidence for the absence of opioid addiction in MOP-receptor knockout rodents even after prolonged morphine treatment18-20. In parallel, opioid-induced behavioural non-analgesic effects such as sedation21 and euphoria 22 have been also well documented in the literature, although usually noted as opioid side effects. Nevertheless, since the analgesic effects of opioids have attracted much of the attention, many other opioid receptor-mediated behavioural effects have been therapeutically underestimated or ignored.

 2 Depression, Anxiety and Pain: more than a triangle

Clinical depression is a common mood disorder that is characterized by behavioural and cognitive symptoms such as disturbances in mood, sleep and eating behaviour, loss of interest, loss of pleasure (anhedonia), decreased energy, feelings of guilt, helplessness, worthlessness and general emotional instability. Depression affects more than 1 in 20 people in developed countries, and more than 350 million people worldwide in 201223. The current antidepressant pharmacotherapies, which include the use of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidation inhibitors (MAOIs) and tricyclic antidepressants (TCAs), are based on the monoamine theory of clinical depression, which links the development of depression with lower levels of dopamine, serotonin and noradrenalin levels in certain brain areas24.

However, current antidepressant therapy remains a challenge due to the high treatment failure rates among patients (63%) and the general negative attitude towards using these agents from both patients and their partners due to their potent behavioural side-effects 25. Both of those issues justify the need to explore novel ideas that could explain the pathology of depression. They also highlight the urgent need to develop new antidepressants that do not rely on the monoamine theory.

Since the late ‘70s, a connection between untreated or undertreated chronic pain and the development of anxiety-related symptoms has been well established 26. Today we know that the development of a number of different anxiety-related disorders can be caused by untreated and persistent chronic pain, which leads to mood disturbances due the reduced quality of life27,28. Anxiety and depression are usually reported as comorbid conditions, although they possess distinct characteristics29, mainly due to the fact that they share common neurophysiological mechanisms of manifestation and sometimes even common interventions30. In parallel, depression has long been reported as a concomitant condition in chronic untreated pain, although there is a wide range of onset (between 10-90%) among neuropathic pain patients31. More than 75% of depressed patients display symptoms of some kind of untreated pain, whereas patients that suffer from persistent pain are more likely to develop depression32. A number of published reviews have quite accurately described the relationship between pain and depression in the literature at all levels of clinical science; diagnosis, symptomatology, clinical outcomes and treatment23-36

Although today, there is still a “chicken & egg” type of discussion regarding the causal relationship between pain, anxiety and depression, a significant clinical association between these three conditions is widely accepted (Figure 1). Their pharmacological treatments have attracted particular attention since they share common efficacies; effective anxiolytics show efficacy against depression and chronic pain, and vice versa37-39. Nevertheless, the use of clinically used opioids for the treatment of anxiety and depression in particular, has not been explored sufficiently, although the euphoric effects of opioids have been described since the late ‘70s40

3 Opioids as antidepressants: how close are we?

The antidepressant effects of opioids have been explored extensively during the last few decades as shown in Table 2 (for a detailed review see Berrocoso et al 41). However, not much progress has been made towards developing novel opioids as antidepressants or even exploring the clinical use of currently available opioids for the treatment of mood disorders like depression.  Despite a large volume of in vitro and in vivo studies in the literature regarding the effects of opioids on serotonergic and dopaminergic biology, only a few studies have explored the antidepressant potential of opioids in clinical trials.

Buprenorphine, a KOP receptor antagonist and a weak MOP agonist, is one such example. The role of the KOP receptors and its associated ligands in anxiety-related conditions has been studied extensively in vitro and in vivo42. A number of studies confirmed antidepressant effects of laboratory KOP receptor antagonists (such as norbinaltorphimine and JDtic) in various preclinical in vivo models of depressive-like behaviour, such as the force swimming test and the learned-helplessness paradigm43-45. In humans, low dose buprenorphine use exhibited antidepressant effects within the first 3 weeks of treatment in adults with treatment-resistant depression46. Currently two opioid ligands as one therapeutic regimen are tested in a Phase II clinical trial as an antidepressant treatment by the biopharmaceutical company Alkermes. The ALKS 5461 is a combination of buprenorphine and samidorphan (a selective MOP antagonist), in an effort to promote buprenorphine’s KOP receptor antagonistic actions by simultaneously blocking it’s MOP receptor specific action and therefore inhibiting it’s potential addictive effects47.  Another opioid that has been tested in clinical trials against depression is the atypical opioid tramadol (a MOP receptor agonist and a serotonin-noradrenaline reuptake inhibitor), which exhibited an antidepressant effect comparable to venlafaxine, a clinically-used serotonin-norepinephrine reuptake inhibitor for the treatment of depression48. Tramadol’s mechanism of action as a weak MOP receptor agonist, which promotes analgesia, and as an agent that increases serotonin and noradrenaline concentrations in the brain, has been thought to be ideal to make it a first in the clinic as an antidepressant49.

Since co-administration of tramadol with current antidepressants has been suggested to present an increased risk of manifested serotonergic syndrome50, the therapeutic use of tramadol monotherapy in patients with depression has not been further explored extensively in double-blind clinical trials. In addition, other atypical opioids (like tapentadol; a MOP receptor agonist and a noradrenaline reauptake-inhibitor) have not been evaluated in vivo for any potential advantages as antidepressants. Although there is a large pool of preclinical studies that show a strong correlation between the MOP & DOP receptor activation and the increased activity of serotonergic/dopaminergic pathways 41, the clinical exploration of MOP and DOP receptor agonists as potential antidepressants has been quite slow.  A limited number of studies have explored the clinical use of MOP agonists like oxycodone and oxymorphone in depression51 whereas disturbance of beta-endorphin levels in depressed patients has been linked with specific clinical symptoms like severe anxiety, phobia and obsession 52. Clinical studies using MOP agonists or antagonists against depression are scarce. Similarly, although there is a large number of preclinical in vivo studies that have confirmed the key role of DOP receptor agonism in the manifestation of antidepressant-like behaviour53-56, clinical studies on DOP agonists are also rare. 

In addition, the pharmacological trend of turning away from peptidic opioids towards non-peptidic analogues, brought the limitations of manifested convulsions for some DOP receptor agonists to the surface, although these could be prevented by a slow dose-escalation strategy57,58. Overall, the unexplored molecular mechanisms of MOP and DOP receptor-mediated antidepressant effects remains a major hindrance for the development of novel opioids that will possess higher antidepressant efficacy.  

The fact that latest epidemiological figures show that more than 50% of patients do not respond to current first-line antidepressant treatment, highlights the fact that there is an intense need for novel, more efficacious and fast-acting antidepressants that exploit new mechanisms of antidepressant activity59. Based on the current pipeline in commercial pharmaceutical development, it seems that there is the will to address this need. A significant number of non-monaminergic drugs are currently under investigation in in Phase II and III for depression, such as ifepristone (an antiprogestogen contraceptive by Corcept), lanicemine (an N-methyl-d-aspartate receptor antagonists  by AstraZeneca), esketamine (a ketamine enantiomer and an  NMDA antagonist by Janssen-Cilag), RG1578 (a negative modulator of metabotropic glutamate 2/3 receptor by Roche), MK-6096 (an orexin 1 & 2 antagonist by Merck) among others47.  However, none of these are opioid or opioid-receptor mediated ligands. The only ligand which is currently in trials as a potential therapeutic agent for major depression and can be somehow linked to opioid action is the agent LY2940094 (a nociceptin antagonist by Lilly) with Phase-I pharmacokinetic studies being concluded in November 2011, followed by a Phase-II study  (8-week administration, randomized, double-blinded, placebo-controlled, parallel-group, multi-centered) for the efficacy and safety of the ligand in patients with depressive disorder, concluded recently in March 2014. Although no results have been published yet from these studies, the company conducted a third Phase-I study looking at the occupancy of nociceptin receptors by the LY2940094 ligand in healthy subjects as well as a second Phase-II study looking at the efficacy of the drug to reduce alcohol dependency (both concluded in December 2014). Although the relationship between the nociceptin receptor and stress responses has been described in the literature and the use of nociceptin antagonists as antidepressant agents has been proposed based on data from animal studies60-62, similarly to classical opioid ligands, there is still an obvious absence of novel opioid ligands in clinical trials for the treatment of depression.

4 Conclusion

Although a large volume of preclinical studies support the antidepressant activity of opioids, it does not appear that novel opioids are currently under development for the treatment of depression, let alone close to clinical trials. Even though there is a good amount of experimental in vivo evidence that supports the beneficial use of opioids in depression and anxiety, it is possible that the addictive properties of opioids as well as their tendency to produce tolerance of their resulted effect from long-term use,  remains a point of concern that averts these agents from developed further. Perhaps the opioid research community needs time to reflect on recent advances in opioid pharmacology, both in non-addictive opioid ligands and opioid/non-opioid dual ligands, in order to set appropriate strategies in the future that will lead to the initiation of clinical studies, either as opioid monotherapies or as a co-treatment with current antidepressants.

5 Competing interest 

None

6 Author’s contributions

XY and ND researched the literature and drafted the manuscript. NG and ND provided conceptual input and proof read the manuscript.

7 References

  1. Dietis N, Rowbotham DJ and Lambert DG. Controlling cancer pain: Is morphine the best we can do? Trends in Anaesthesia and Critical Care 2011; (1): 227-229.
  2. Cherubino P, Sarzi-Puttini P, Zuccaro SM and Labianca R. The management of chronic pain in important patient subgroups. Clin Drug Investig. 2012; 32(1): 35-44.
  3. Greco MT, Roberto A, Corli O, Deandrea S, Bandieri E, Cavuto S and Apolone G. Quality of Cancer Pain Management: An Update of a Systematic Review of Undertreatment of Patients With Cancer. J Clin Oncol. 2014; 32 (36): 4149-4154.
  4. Pergolizzi JV, Gharibo C and Ho KY. Treatment Considerations for Cancer Pain: A Global Perspective. Pain Pract. 2014; doi: 10.1111/papr.12253 (ahead of print).
  5. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R, Loeser JD, Payne R and Torebjork E. Towards a mechanism-based classification of pain. Pain. 1998; 77(3): 227-229.
  6. Woolf CJ and Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. The Lancet. 1999; 353(9168): 1959-1964.
  7. Urch CE, Suzuki R, Higginson IJ, Hearn J, Murtagh F, Twycross R, et al.. Pathophysiology of somatic, visceral, and neuropathic cancer pain. Clinical Pain Management Second Edition: Cancer Pain. 2008; 3(4): 13.
  8. Dietis N, Rowbotham DJ and Lambert DG. Opioid receptor subtypes: fact or artifact? Br J Anaesth. 2011;107(1): 8-18.
  9. Kieffer BL and Gavériaux-Ruff C. Exploring the opioid system by gene knockout. Prog Neurobiol. 2002; 66(5):285-306.
  10. Lambert DG. The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov. 2008; 7(8):694-710.
  11. Terman G and Bonica J. Spinal mechanisms and their modulation. Bonica’s Management of Pain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins: 2001;73-152.
  12. Inturrisi CE. Clinical pharmacology of opioids for pain. The Clinical journal of pain. 2002; 18(4): S3-S13.
  13. Mattia C. Editorial: non-analgesic effects of opioids: the dark side of the moon. Curr Pharm Des. 2012; 18(37): 5991-3.
  14. Gutstein HB and Akil H. Opioid analgesics. Goodman and Gilman`s The Pharmacological Basis of Therapeutics, 10th ed. Edited by Hardman JG, Limbird LE, Gilman AG. New York, McGraw-Hill2001; 569-620.
  15. Nestler EJ. Molecular neurobiology of addiction. The American journal on addictions. 2001; 10(3): 201-217.
  16. Kovoor A, Henry DJ and Chavkin C. Agonist-induced desensitization of the mu opioid receptor-coupled potassium channel (GIRK1). Journal of Biological Chemistry. 1995; 270(2): 589-595.
  17. Mestek A, Hurley JH, Bye LS, Campbell AD, Chen Y, Tian M, Liu J, Schulman H and Yu L.The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C. The journal of neuroscience. 1995; 15(3): 2396-2406.
  18. Berrendero F, Kieffer BL and Maldonado R. Attenuation of nicotine-induced antinociception, rewarding effects, and dependence in μ-opioid receptor knock-out mice. The journal of neuroscience. 2002;22(24): 10935-10940.
  19. Gaveriaux-Ruff C and Kieffer B. Opioid receptor genes inactivated in mice: the highlights. Neuropeptides. 2002; 36(2): 62-71.
  20. Hough L, Nalwalk JW, Chen Y, Schuller A, Zhu Y, Zhang J, Menge WM, Leurs R, Timmerman H and Pintar JE. Improgan, a cimetidine analog, induces morphine-like antinociception in opioid receptor-knockout mice. Brain research. 2000; 880(1): 102-108.
  21. Smith A, Farrington M and Matthews G. Monitoring sedation in patients receiving opioids for pain management. J Nurs Care Qual. 2014; 29(4): 345-53.
  22. Jasinski DR and Preston KL. Evaluation of tilidine for morphine-like subjective effects and euphoria. Drug Alcohol Depend. 1986; 18(3): 273-92.
  23. World Health Organization (WHO), World suicide prevention day 2012.   http://www.who.int/mediacentre/events/annual/world_suicide_prevention_day/en. Accessed 16.6.2012
  24. Elhwuegi AS. Central monoamines and their role in major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2004; 28(3): 435-451.
  25. Kessing LV, Vibe Hansen H, Demyttenaere K and Bech P. Depressive and bipolar disorders: patients` attitudes and beliefs towards depression and antidepressants. Psychological medicine. 2005; 35(08): 1205-1213.
  26. Jones LP. Anxiety, as experienced by chronic pain patients. J Relig Health. 1985; 24(3): 209-17.
  27. Jordan KD and Okifuji A.  Anxiety disorders: differential diagnosis and their relationship to chronic pain. J Pain Palliat Care Pharmacother. 2011; 25(3): 231-45.
  28. Asmundson GJ. Anxiety and related factors in chronic pain. Pain Res Manag. 2002; 7(1): 7-8.
  29. Nelson DV and Novy DM. Self-report differentiation of anxiety and depression in chronic pain. J Pers Assess. 1997; 69(2): 392-407.
  30. Adamek ME and Slater GY. Depression and anxiety. J Gerontol Soc Work. 2008; 50 Suppl 1: 153-89.
  31. Turkington RW. Depression masquerading as diabetic neuropathy. Jama. 1980; 243(11): 1147-1150.
  32. Lepine JP and Briley M. The epidemiology of pain in depression. Hum Psychopharmacol. 2004; 19 Suppl 1: S3-7.
  33. Bair M, Robinson R, Katon W and Kroenke K. Depression and pain comorbidity. Ach Intern Med. 2003; 163: 2433-2445.
  34. Dickens C, McGowan L and Dale S. Impact of depression on experimental pain perception: a systematic review of the literature with meta-analysis. Psychosom Med. 2003; 65(3): 369-75.
  35. Rijavec N and Grubic VN. Depression and pain: often together but still a clinical challenge: a review. Psychiatr Danub. 2012; 24(4): 346-52.
  36. Holmes A, Christelis N and Arnold C. Depression and chronic pain. MJA Open. 2012; 1 Suppl 4: 17-20.
  37. King RB. Neuropharmacology of depression, anxiety, and pain. Clin Neurosurg. 1981; 28:116-36.
  38. Verma S and Gallagher RM. The psychopharmacologic treatment of depression and anxiety in the context of chronic pain. Curr Pain Headache Rep. 2002; 6(1): 30-9.
  39. Jongen JL, Hans G, Benzon HT, Huygen F and Hartrick CT. Neuropathic pain and pharmacological treatment. Pain Pract. 2014; 14(3):283-95.
  40. Levitt RA, Baltzer JH, Evers TM, Stilwell DJ and Furby JE. Morphine and shuttle-box self-stimulation in the rat: a model for euphoria. Psychopharmacology (Berl). 1977; 54(3): 307-11.
  41. Berrocoso E, Sánchez-Blázquez P, Garzón J and Mico JA. Opiates as antidepressants. Current pharmaceutical design. 2009; 15(14): 1612-1622.
  42. Van`t Veer A and Carlezon WA Jr.  Role of kappa-opioid receptors in stress and anxiety-related behavior. Psychopharmacology (Berl). 2013; 229(3): 435-52.
  43. Beardsley PM, Howard JL, Shelton KL and Carroll FI. Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in  rats. Psychopharmacology. 2005; 183:118–126.
  44. McLaughlin JP, Li S, Valdez J, Chavkin TA and Chavkin C. Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system. Neuropsychopharmacol. 2006; 31: 1241–1248.
  45. Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ and Chavkin C. The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. J Neurosci. 2008; 28: 407–414.
  46. Karp JF, Butters MA, Begley AE, Miller MD, Lenze EJ, Blumberger DM, Mulsant BH and Reynolds CF. Safety, tolerability, and clinical effect of low-dose buprenorphine for treatment-resistant depression in midlife and older adults. J Clin Psychiatry. 2014; 75(8): e785-93.
  47. Harrison C. Nature Reviews Drug Discovery. Trial watch: Opioid receptor blocker shows promise in Phase II depression trial. 2013; 12: 415.
  48. Shapira NA, Verduin ML and DeGraw JD. Treatment of refractory major depression with tramadol monotherapy. J Clin Psychiatry. 2001; 62(3): 205-6.
  49. Barber J. Examining the use of tramadol hydrochloride as an antidepressant. Exp Clin Psychopharmacol. 2011; 19(2): 123-30.
  50. Shahani L. Tramadol precipitating serotonin syndrome in a patient on antidepressants. J Neuropsychiatry Clin Neurosci. 2012; 24(4): E52.
  51. Stoll AL and Rueter S. Treatment augmentation with opiates in severe and refractory major depression. Am J Psychiatry. 1999; 156(12): 2017.
  52. Darko DF, Risch SC, Gillin JC and Golshan S. Association of beta-endorphin with specific clinical symptoms of depression. Am J Psychiatry. 1992; 149(9): 1162-7.
  53. Baamonde A, Daugé V, Ruiz-Gayo M, Fulga, IG, Turcaud S, Fournié-Zaluski MC and Roques BP. Antidepressant-type effects of endogenous enkephalins protected by systemic RB 101 are mediated by opioid δ and dopamine D1 receptor stimulation. Eur. J. Pharmacol. 1992; 216: 157–166
  54. Tejedor-Real P, Micó JA, Smadja C, Maldonado R., Roques BP and Gibert-Rahola J. Involvement of δ-opioid receptors in the effects induced by endogenous enkephalins on learned helplessness model. Eur. J. Pharmacol. 1998; 354: 1–7.
  55. Torregrossa MM, Jutkiewicz EM, Mosberg HI, Balboni G, Watson SJ and Woods JH. Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats. Brain Res. 2006; 1069: 172–181.
  56. Saitoh A, Yamada M, Yamada M, Takahashi K, Yamaguchi K, Murasawa H, Nakatani A, Tatsumi Y, Hirose N and Kamei J. Antidepressant-like effects of the delta-opioid receptor agonist SNC80 ([(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide) in an olfactory bulbectomized rat model. Brain Res. 2008; 1208: 160-9.
  57. Broom DC, Jutkiewicz EM, Rice KC, Traynor JR and Woods JH. Behavioral effects of delta-opioid receptor agonists: potential antidepressants? Jpn J Pharmacol. 2002; 90(1):1-6.
  58. Jutkiewicz EM. The antidepressant -like effects of delta-opioid receptor agonists. Mol Interv. 2006; 6(3):162-9.
  59. O`Leary OF, Dinan TG and Cryan JF. Faster, better, stronger: Towards new antidepressant therapeutic strategies. Eur J Pharmacol. 2014; pii: S0014-2999(14)00584-6 (ahead of print).
  60. Gavioli EC and Calo G.  Nociceptin/orphanin FQ receptor antagonists as innovative antidepressant drugs. Pharmacol Ther. 2013; 140(1):10-25.
  61. Vitale G, Ruggieri V, Filaferro M, Frigeri C, Alboni S, Tascedda F, Brunello N, Guerrini R, Cifani C and Massi M. Chronic treatment with the selective NOP receptor antagonist [Nphe 1, Arg 14, Lys 15]N/OFQ-NH 2 (UFP-101) reverses the behavioural and biochemical effects of unpredictable chronic mild stress in rats. Psychopharmacology (Berl). 2009; 207(2):173-89.
  62. Gavioli EC, Marzola G, Guerrini R, Bertorelli R, Zucchini S, De Lima TC and Rae GA, Salvadori S, Regoli D, Calo G. Blockade of nociceptin/orphanin FQ-NOP receptor signalling produces antidepressant-like effects: pharmacological and genetic evidences from the mouse forced swimming test. Eur J Neurosci. 2003; 17(9):1987-90.
  63. Tejedor-Real P, Mico JA, Maldonado R, Roques BP and Gibert-Rahola J. Implication of endogenous opioid system in the learned helplessness model of depression. Pharmacology Biochemistry and Behavior. 1995; 52(1): 145-152.
  64. Stoll AL and Rueter S. Treatment augmentation with opiates in severe and refractory major depression. American Journal of Psychiatry. 1999; 156(12): 2017-2017.
  65. Berrocoso E, Ikeda K, Sora I, Uhl GR, Sánchez-Blázquez P and Mico JA. Active behaviours produced by antidepressants and opioids in the mouse tail suspension test. International Journal of Neuropsychopharmacology. 2013; 16(1): 151-162.
  66. Berrocoso E. and Mico JA. Cooperative opioid and serotonergic mechanisms generate superior antidepressant-like effects in a mice model of depression. International Journal of Neuropsychopharmacology. 2009; 12(8): 1033-1044.
  67. Emrich, H, Vogt P and Herz A. Possible antidepressive effects of opioids: action of buprenorphine. Annals of the New York Academy of Sciences. 1982; 398(1): 108-112.
  68. Bodkin JA, Zornberg GL, Lukas SE and Cole JO. Buprenorphine treatment of refractory depression. Journal of clinical psychopharmacology. 1995; 15(1): 49-57.
  69. Nemeroff, C.B., Prevalence and management of treatment-resistant depression. Journal of Clinical Psychiatry. 2007; 68(8): 17.
  70. Shapira, NA, Verduin ML and DeGraw JD. Treatment of refractory major depression with tramadol monotherapy. 2001.
  71. Rojas-Corrales M, Berrocoso E, Gibert-Rahola J and Micó JA. Antidepressant-like effects of tramadol and other central analgesics with activity on monoamines reuptake, in helpless rats. Life sciences. 2002; 72(2): 143-152.
  72. Yalcin I, Aksu F, Bodard S, Chalon S and Belzung C. Antidepressant-like effect of tramadol in the unpredictable chronic mild stress procedure: possible involvement of the noradrenergic system. Behavioural pharmacology. 2007; 18(7): 623-631.
  73. Jesse CR, Bortolatto CF, Savegnago L, Rocha JB and Nogueira CW. Involvement of l-arginine–nitric oxide–cyclic guanosine monophosphate pathway in the antidepressant-like effect of tramadol in the rat forced swimming test. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2008; 32(8): 1838-1843.
  74. Terenius, L, Wahlstrom A and Agren H. Naloxone (Narcan®) treatment in depression: clinical observations and effects on CSF endorphins and monoamine metabolites. Psychopharmacology. 1977; 54(1): 31-33.
  75. Hunziker ML. Opioid nature of learned helplessness and stress-induced analgesia observed without re-exposure to shock. Behavioural Pharmacology, 1992; 3(2): 117-122.
  76. Salloum, IM, Cornelius JR, Thase ME, Daley DC, Kirisci L and Spotts C. Naltrexone utility in depressed alcoholics. Psychopharmacology Bulletin, 1997; 34(1): 111-115.
  77. Grahn RE, Maswood S, McQueen MB, Watkins LR and Maier SF. Opioid-dependent effects of inescapable shock on escape behavior and conditioned fear responding are mediated by the dorsal raphe nucleus. Behavioural brain research, 1999; 99(2): 153-167.