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