SciELO - Scientific Electronic Library Online

 
vol.28 número3Evaluación de la relación entre rasgos psicopatológicos de la personalidad y la calidad del sueñoEvaluación del componente afectivo de la depresión: análisis factorial del ST/DEP revisado índice de autoresíndice de materiabúsqueda de artículos
Home Pagelista alfabética de revistas  

Servicios Personalizados

Revista

Articulo

Indicadores

Links relacionados

  • No hay artículos similaresSimilares en SciELO

Compartir


Salud mental

versión impresa ISSN 0185-3325

Salud Ment vol.28 no.3 México may./jun. 2005

 

Artículos originales

Mecanismos de tolerancia analgésica a los opioides

Gloria P. Hernández-Delgadillo1 

Silvia L. Cruz2 

1Facultad de Medicina Humana, Universidad Autónoma de Zacatecas.

2Departamento de Farmacobiología, Cinvestav, IPN.

Resumen:

Los agonistas opioides producen analgesia a través de su interacción con receptores específicos acoplados a proteínas Gi/o. Agudamente, inhiben la vía de la adenilato ciclasa, activan canales de potasio y bloquean canales de calcio, dando como resultado una hiperpolarización celular. Los opioides también activan la vía de la fosfolipasa C, pero éste es un efecto excitatorio de corta duración. La tolerancia a sus efectos analgésicos se presenta después de administraciones repetidas y es un efecto indeseable que limita su utilidad en la práctica clínica. En esta revisión, se presentan los mecanismos propuestos para explicar este fenómeno y los fármacos usados para atenuarlo, prevenirlo y/o revertirlo.

La tolerancia involucra la participación de diversos sistemas de neurotransmisión y adaptaciones a diferentes niveles subcelulares. No parece tratarse de un fenómeno farmacocinético, ya que en los pacientes que han recibido tratamientos crónicos y agudos con opioides no se observan diferencias significativas en sus metabolitos. La administración crónica de opioides produce cam bios en el nivel de los receptores, de segundos mensajeros y de otros sistemas de neurotransmisión. En lo que se refiere al receptor, se han descrito tres procesos: a) desensibilización por fosforilación; b) internalización o endocitosis; y c) degradación. Estos procesos pueden darse en los propios receptores a opioides (cambios homólogos) o en receptores a otros neurotransmisores (cambios heterólogos). Entre las adaptaciones que se presentan en la señalización intracelular, se han descrito las siguientes: una regulación a la alta del sistema de la adenilato ciclasa, un incremento en la activación de los canales de calcio, una pérdida de la activación de los canales rectificadores entrantes de potasio y un aumento en la hidrólisis de los lípidos de inositol. Estos efectos son opuestos a los producidos por la administración aguda de agonistas opioides y como consecuencia activan varias enzimas, entre las que destacan la proteína cinasa dependiente de AMPc (PKA), la proteína cinasa dependiente de calcio (PKC), la ciclooxigenasa (COX), en particular de la isoforma COX-2, y la sintasa del óxido nítrico (SON).

Dado que la activación de algunos sistemas fisiológicos antagoniza varios efectos agudos de los opioides, se ha propuesto que durante el desarrollo de tolerancia analgésica se produce un incremento de péptidos antiopioides, como la colecistocinina (CCK), el neuropéptido FF y la orfanina FQ. De la misma manera, hay evidencias muy sólidas que indican que la activación de los receptores NMDA cumple un papel importante en la tolerancia analgésica a los opioides porque los antagonistas de este tipo de receptor previenen y/o revierten este fenómeno. También se ha propuesto que la administración crónica de opioides da como resultado la activación de los sistemas descendentes facilitatorios del dolor. Si bien se acepta que la tolerancia es un fenómeno complejo que involucra diversas variables, parece claro que los procesos relacionados con el incremento del calcio en el nivel intracelular desempeñan un papel determinante.

En estudios preclínicos se han descrito varios fármacos que previenen, retardan o disminuyen el desarrollo de tolerancia analgésica cuando se administran junto con los opioides. Entre las estrategias farmacológicas propuestas para disminuir la tolerancia se encuentran las siguientes: a) el uso de antagonistas competitivos y no competitivos de los receptores NMDA; b) la coadministración de dosis terapéuticas de agonistas opioides con dosis muy bajas de antagonistas opioides; c) el uso de inhibidores enzimáticos, en particular de COX-2; y d) la co-administración de agonistas µ con agonistas 5 para favorecer la endocitosis de los receptores opioides y evitar así que se induzcan los cambios de señalización intracelular producidos cuando sólo se administra morfina. Entre las estrategias fisiológicas se encuentran el espaciamiento correcto entre dosis y el mantenimiento de niveles terapéuticos para evitar la presentación de picos y valles que dificulten el control del dolor y promuevan un incremento no justificado de las dosis de opioides.

Palabras clave: Tolerancia; analgesia; opioides; mecanismos; revisión

Abstract:

Opioid agonists medíate their analgesic effects by interacting with Gi/o protein-coupled receptors. Acute opioid administration produces: a) an inhibition of the adenylate cyclase (AC) pathway; b) an activation of G-coupled inwardly rectifying potassium channels (GIRKs); and c) a blockade of voltage-dependent calcium channels. All these effects result in cell hyperpolarization and neurodepression. In addition, opioids can stimulate the hydrolysis of phosphatidylinositol by activation of phospolipase C with the resulting calcium release from intracellular storages. However, this is a short-lasting excitatory effect.

The development of analgesic tolerance to opioids after repeated administration is an undesirable side effect in clinical practice that limits their use for prolonged treatments. This paper reviews the main mechanisms that have been proposed to play a role in the development of opioid-induced analgesic tolerance, as well as the drugs that have some efficacy in reducing or preventing it.

Tolerance is a complex process involving several neurotransmitter systems and neural adaptations occurring at different levels. It does not seem to be due to metabolic changes because concentrations of the main morphine metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), are not significantly changed in tolerant patients.

There is sound evidence suggesting that the main changes underlying tolerance development are pharmacodynamic in nature. These changes occur at: a) the receptor level; b) the second messenger level; and c) other neurotransmitter systems. At the receptor level, three different processes have been described: 1. phosphorilation-mediated desensitization; 2. (3-arrestin-dependent endocytosis; and 3. receptor down regulation. These processes can affect opioid receptors themselves (homologous changes) and/ or receptors to other neurotransmitters (heterologous changes).

Different researchers have pointed out that there are some inconsistencies between the level of agonist-induced receptor endocytosis and the degree of analgesic tolerance produced by opioid agonists. For example, morphine does not promote efficient receptor internalization, but it produces a strong intracellular signal and, after repeated administrations, a high degree of tolerance. The opposite occurs with other opioids such as DAMGO, methadone and some 5-agonists; i.e., they produce low tolerance, but a high degree of receptor endocytosis. This fact has led to the development of a new theory which proposes that opioid-induced compensatory intracellular changes play an important role in tolerance development.

These compensatory changes are more difficult to reverse than changes occurring at the receptor level, because receptor sequestration does not necessarily commit receptors to degradation, but lead, at least in part, to dephosphorilation and receptor recycling to the cell surface. Based on this, Whistler and coworkers proposed the "RAVE" (Relative Agonist signaling Versus Endocytosis) theory, stating that strong internalization would limit tolerance while sustained signaling would favor it.

Probably the best studied change in intracellular signaling produced by chronic opioid administration is cAMP up-regulation. Acutely, this pathway is inhibited by opioids, but chronic exposure leads to a loss of inhibition of adenylate cyclase. This is due, in part, to a loss of the ability of the agonist-occupied receptor to activate Gi/o proteins and to an increased expression of certain types of adenylate cyclase, protein kinase A (PKA) and cAMP response element binding protein (CREB). Persistent opioid receptor activation also induces an increase in calcium channel activity, a decrease in the activation of G-coupled inwardly rectifying potassium channels (GIRKs), and a stimulation of the phospholipids signal transduction pathways. All these mechanisms have also been proposed to play a role in tolerance development.

Several enzymes can be activated as a result of chronic opioid administration. Among them, phospholipase A2 (PLA2), cyclooxygenase (COX), in particular the COX-2 isoform, and nitric oxide synthase (NOS) are particularly relevant because their activation leads to an increase in prostaglandins and nitric oxide synthesis. Besides, repeated opioid agonist exposure induces an up-regulation of the cAMP-dependent protein kinase (PKA), the calcium-dependent protein kinase (PKC), the calcium calmodulin II dependent kinase and those kinases activated by mitogens (MAPKs). Phosphorylation by these kinases alters the functioning of many different target proteins, including NMDA receptors. When these glutamatergic receptors are phosphorylated, the Mg2+ block is removed and sodium and calcium ions can enter the cell. There is sound evidence indicating that NMDA receptor activation plays an important role in opioid analgesic tolerance because NMDA receptor antagonists prevent and/or delay its development in humans and animals. There is agreement in considering opioid analgesic tolerance as a complex phenomenon, but those changes resulting in an intracellular calcium increase seem to play a particularly relevant role.

Since activation of certain physiological systems may antagonize some acute opioid effects, several investigators have proposed that, as a consequence of chronic opioid administration, endogenous antiopioid peptides are released to maintain the homeostasis. Among them, the best studied peptides are the Tyr-MIF-1 family of peptides, cholecystokinin (CCK), neuropeptide FF (NPFF) and orphanin FQ/nociceptin. Under physiological conditions these systems modulate opioid peptides, but the ba lance can be lost as a result of chronic opioid exposure.

It has also been proposed that chronic opioid administration results in the activation of facilitatory pain descending pathways and that several neurotransmitter systems other than the adrenergic, serotonergic and opioidergic are affected by repeated morphine administration. Their relative impact in analgesic tolerance depends upon the species, the drug and the schedule of opioid administration.

In preclinical studies, several drugs capable of preventing, decreasing or delaying analgesic tolerance when co-administered with opioids, have been identified. Based on this, several pharmacological strategies have been proposed to reduce tolerance. The following can be mentioned: a) administration of competitive and non-competitive NMDA receptor antagonists; b) co-administration of therapeutic opioid agonist doses with very low opioid antagonist doses; c) use of PKC inhibitors and COX inhibitors (in particular those with higher affinity for COX2 isoform); and d) co-administration of u. agonists with other agonists to induce receptor endocytosis thus preventing the induction of more long-lasting intracellular signaling changes. Among the pshysiological approaches, the proper dosification and administration schedule of opioids are crucial factors to prevent an artificial need of dose escalation.

Key words: Tolerance; analgesia; opioids; mechanisms; review

Texto completo disponible solo en PDF

Referencias

1. Aley KO, Levine JD: Multiple receptors involved in peripheral IL and Ai antinociception, tolerance, and withdrawal. J Neurosa, 17(2):735-744, 1997. [ Links ]

2. Antkiewicz-Michaluk L, Michaluk J, Romanska I, Vetulani J: Reduction of morphine dependence and potentiation of analgesia by chronic co-administration of nifedipine. Psychopharmacology, 111:457-464, 1993. [ Links ]

3. Bhargava HN: Diversity of agents that modify opioid tolerance, physical dependence, abstinence syndrome, and self-administrative behavior. Pharmacol Rev, 46:293-324,1994. [ Links ]

4. Cesselin F: Opioid and anti-opioid peptides. Fundam Clin Pharmacol, 9:409-433, 1995. [ Links ]

5. Chakrabarti S, Oppermann M, Gintzler AR: Chronic morphine induces the concomitant phosphorylation and altered association of multiple signaling proteins: a novel mechanism for modulating cell signaling. Proc Natl Acad Sci, 98:4209-4214, 2001. [ Links ]

6. Claing A, Laporte SA, Caron MG, Lefkowitz RJ: Endocytosis of G protein-coupled receptors: roles of G protein-coupled receptor kinases and (3-arrestin proteins. Prog Neurobiol, 66:61-79, 2002. [ Links ]

7. Cox BM: Mechanisms of tolerance. En: Stein C (ed). Opioids in Pain Control. Cambridge University Press, 109-130, Nueva York, 1999. [ Links ]

8. Crain SM, Shen KF: Modulation of opioid analgesia, tolerance and dependence by Gs-coupled, GM1 ganglioside-regulated opioid receptor functions. Trends Pharmacol Sci, 19:358-365, 1998. [ Links ]

9. Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS, Hamon M: International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol Rev, 48:567-592, 1996. [ Links ]

10. Feldman RS, Meyer JS, Quenzer LF: Principies of Neuropsychopharmacology. Sinauer Associates, Massachusetts, 1997. [ Links ]

11. Ferguson SSG: Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev, 53:1-24, 2001. [ Links ]

12. Gaveriaux-Ruff C, Kieffer B: Opioid receptors: gene structure and function. En: Stein C (ed). Opioids in Pain Control. Cambridge University Press, 1-20, Nueva York, 1999. [ Links ]

13. Gonzalez LG, Portillo E, Del Pozo E, Baeyens JM: Changes in [3H]glibenclamide binding to mouse forebrain membranes during morphine tolerance. Eur J Pharmacol, 418:29-37, 2001. [ Links ]

14. Gutstein HB, Akil H: Opioid analgesics. En: Hardman JG, Limbird LE, Goodman Gilman A (eds). Goodman & Gilman's The Pharmacological Basis of Therapeutics. McGraw Hill, 569-619, Nueva York, 2001. [ Links ]

15. Haigh RC, Blake DR: Understanding pain. Clin Med, 1:44-48, 2001. [ Links ]

16. Harrison LM, Kastin AJ, Zadina JE: Opiate tolerance and dependence: receptors, G-proteins, and antiopiates. Peptides, 19:1603-1630, 1998. [ Links ]

17. Hernández-Delgadillo GP, Cruz SL: Dipyrone potentiates morphine-induced antinociception in dipyrone-treated and morphine-tolerant rats. Eur J Pharmacol, 502:67-73, 2004. [ Links ]

18. Hernández Delgadillo GP, López-Muñoz FJ, Salazar LA, Cruz SL: Morphine and dipyrone co-administration delays tolerance development and potentiates antinociception. Eur J Pharmacol, 469:71-79, 2003. [ Links ]

19. Hernandez-Delgadillo GP, Ventura-Martínez R, Diaz Reval MI, Dominguez Ramírez AM, López-Muñoz FJ: Metamizol potentiates opiate antinociception but not constipation after chronic treatment. Eur J Pharmacol, 441:177-183, 2002. [ Links ]

20. Keith DE, Murray SR, Zaki PA, Chu PC, Lissin DV, Kang L, Evans CJ, Von Zastrow M: Morphine activates opioid receptors without causing their rapid internalization. J Biol Chem, 277:19021-19024, 1996. [ Links ]

21. Kieffer BL, Evans CJ: Opioid tolerance- In search of the Holy Grail. Cell, 108:587-590, 2002. [ Links ]

22. Kolesnikov Y, Pasternak GW: Topical opioids in mice: Analgesia and reversal of tolerance by a topical N-methyl-D-aspartate antagonist. J Pharmacol Exp Ther, 290:247-252, 1999. [ Links ]

23. Kovoor A, Henry DJ, Chavkin C: Agonist-induced desensitization of the mu opioid receptor-coupled potassium channel (GIRK1). J Biol Chem, 270:589-595, 1995. [ Links ]

24. Law PY, Wong YH, Loh HH: Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol, 40:389-430, 2000. [ Links ]

25. Liu JG, Anand KJS: Protein kinases modulate the celular adaptations associated with opioid tolerance and dependence. Brain Res Rev, 38:1-19, 2001. [ Links ]

26. Lopez-Muñoz FJ. Surface of synergistic interaction between dipyrone and morphine in the PIFIR model. Drug Dev Res, 33:26-32, 1994. [ Links ]

27. Mao J: NMDA and opioid receptors: their interactions in antinociception, tolerance and neuroplasticity. Brain Res Rev, 30:289-304, 1999. [ Links ]

28. Mao J, Mayer DJ: Spinal cord neuroplasticity following repeated opioid exposure and its relation to pathological pain. Ann N Y Acad Sci, 933:175-184, 2001. [ Links ]

29. Mao J, Sung B, Ji RR, Lim G: Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism. J Neurosci, 22(17):7650-7661, 2002b. [ Links ]

30. Mayer DJ, Mao J, Holt J, Price DD: Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. Proc Natl Acad Sci, 96:7731-7736, 1999. [ Links ]

31. Millan MJ: Descending control of pain. Prog Neurobiol, 66:355-474, 2002. [ Links ]

32. Morgan MM, Clayton CC, Lane DA: Behavioral evidence linking opioid-sensitive GABAergic neurons in the ventrolateral periaqueductal gray to morphine tolerance. Neuroscience, 118:227-232, 2003. [ Links ]

33. Nishino K, Su YF, Wong CS, Watkins WD, Chang KJ: Dissociation of mu opioid tolerance from receptor down-regulation in rat spinal cord. J Pharmacol Exp Ther, 253:67-72, 1990. [ Links ]

34. Ohnishi T, Saito K, Maeda S, Matsumoto K, Sakuda M, Inoki R: Intracerebroventricular treatment of mice with pertussis toxin induces hyperalgesia and enhances 3H-nitrendipine binding to synaptic membranes: similarity with morphine tolerance. Naunyn-Schmiedeberg's Arch Pharmacol, 341:123-127, 1990. [ Links ]

35. Ouellet DMC, Pollack GM: Effect of prior morphine-3-glucuronide exposure on morphine disposition and antinociception. Biochem Pharmacol, 53:1451-1457, 1997. [ Links ]

36. Polastron J, Meunier JC, Jauzac P: Chronic morphine induces tolerance and desensitization of I -opioid receptor but not down-regulation in rabbit. Eur J Pharmacol, 266:139-146,1994. [ Links ]

37. Puttfarcken PS, Cox BM: Morphine-induced desensitization and down-regulation at mu-receptors in 7315C pituitary tumor cells. Life Sci, 45:1937-1942, 1989. [ Links ]

38. Raith K, Hochhaus G: Drugs used in the treatment of opioid tolerance and physical dependence: a review. Int J Clin Pharmacol Ther, 42:191-203, 2004. [ Links ]

39. Rohde DS, Basbaum AI: Activation of coeruleospinal noradrenergic inhibitory controls during withdrawal from morphine in the rat. J Neurosci, 18(11):4393-4402, 1998. [ Links ]

40. Rothman RB: A review of the role of anti-opioid peptides in morphine tolerance and dependence. Synapse, 12:129-138, 1992. [ Links ]

41. Santillan R, Hurle MA, Armijo JA, Mozos R, Florez J: Nimodipine-enhanced opiate analgesia in cancer patients requiring morphine dose escalation: a double-blind, placebo-controlled study. Pain, 76:17-26, 1998. [ Links ]

42. Smith FL, Dombrowski DS, Dewey WI: Involvement of intracellular calcium in morphine tolerance in mice. Pharmacol Biochem Behav, 62:381-388, 1999a. [ Links ]

43. Smith FL, Lohmann AB, Dewey WL: Involvement of phospholipid signal transduction pathways in morphine tolerance in mice. Br J Pharmacol, 128:220-226, 1999b. [ Links ]

44. Tang WJ, Hurley JH: Catalytic mechanism and regulation of mammalian adenylyl cyclases. Mol Pharmacol, 54:231-240, 1998. [ Links ]

45. Trujillo KA: Are NMDA receptors involved in opiate-induced neural and behavioral plasticity?. A review of preclinical studies. Psychopharmacology, 151:121-141, 2000. [ Links ]

46. Trujilllo KA, Akil H: Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science, 251:85-87, 1991. [ Links ]

47. Ueda H, Inoue M, Mizuno K: New approaches to study the development of morphine tolerance and dependence. Life Sci, 74:313-320, 2003. [ Links ]

48. Vanderah TW, Ossipov MH, Lai J, Malan TP, Porreca F: Mechanisms of opioid-induced pain and antinociceptive tolerance: descending facilitation and spinal dynorphin. Pain, 92:5-9, 2001. [ Links ]

49. Varga EV, Yamamura HI, Rubenzik MK, Tropova D, navratilova E, Roeske WR: Molecular mechanisms of excitatory signaling upon chronic opioid agonist treatment. Life Sci, 74:299-311, 2003. [ Links ]

50. Villanueva L, Le Bars D: The activation of bulbo-spinal controls by peripheral nociceptive inputs: diffuse inhibitory controls. Biol Res, 28:113-125, 1995. [ Links ]

51. Waldhoer M, Bartlett SE, Whistler JI: Opioid receptors. Annu Rev Toxicol, 73:953-990, 2004. [ Links ]

52. Watts VJ: Molecular mechanisms for heterologous sensitization of adenylate cyclase. J Pharmacol Exp Ther, 302:1-7, 2002. [ Links ]

53. Welch SP, Olson KG: Opiate tolerance-inducedmodulation of free intracellular calcium in synaptosomes.Life Sci, 48:1853-1861, 1991. [ Links ]

54. Whistler JL, Chuang HH, Chu P, Jan LY, Von Zastrow M: Functional dissociation of mu opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction. Neuron, 23:737-746, 1999. [ Links ]

55. Whistler JL, Enquist J, Marley A, Fong J, Gladher F, Tsuruda P, Murray SR, Von Zastrow M: Modulation of postendocytic sorting of G protein-coupled receptors. Science, 297:615-620, 2002. [ Links ]

56. Williams JT, Christie MJ, Manzoni O: Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev, 81:299-343, 2001. [ Links ]

57. Wong CS, Hsu MM, Chou R, Chou YY, Tung CS: Intrathecal cyclooxygenase inhibitor administration attenuates morphine antinociceptive tolerance in rats. Br J Anaesth, 85:747-751, 2000a. [ Links ]

58. Wong CS, Hsu MM, Chou YY, Tao PL, Tung CS: Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord. Br J Anaesth, 85:587-591, 2000b. [ Links ]

59. Zadina JE, Kastin AJ, Harrison LM, Ge LJ, Chang SL: Opiate receptor changes after chronic exposure to agonists and antagonists. Ann N Y Acad Sci, 757:353-361, 1995. [ Links ]

Recibido: 10 de Marzo de 2005; Aprobado: 14 de Abril de 2005

Correspondencia: Silvia L. Cruz. Calzada de los Tenorios 235, Col. Granjas Coapa, 14330, México DF. Tel: 5061-2853; Fax: 5061-2863. Email: cruz_farma@yahoo.com

Creative Commons License Este es un artículo publicado en acceso abierto bajo una licencia Creative Commons