Pain Forum最新文献

Although opioids are the most commonly used analgesics, their therapeutic efficacy is limited by the development of tolerance and dependence with chronic use. Many studies have examined the possible mechanisms underlying the development of opioid tolerance and dependence. Recently, several groups of investigators have focused on excitatory amino acid receptors, specifically N-methyl-D-aspartate (NMDA) receptors, and related intracellular second messenger systems as possible mediators of opioid tolerance and dependence. The hypothesis proposed in this Focus article is an extension of these models of opioid tolerance and dependence, which suggests that metabotropic glutamate receptors (mGluRs) play a key role in the development of opioid tolerance and dependence. We propose that activity at group I mGluRs (and possibly also δ-opioid receptors), which are positively coupled to phosphatidylinositol (PI) hydrolysis, increases during chronic morphine administration. This ultimately leads to increased activation of protein kinase C, with concomitant phosphorylation of μ-opioid receptors (desensitizing them), and the ion channel associated with the NMDA receptor (allowing increased influx of Ca²⁺). We also suggest that there is a heterologous desensitization of group II and III mGluRs, which are negatively coupled to cyclic adenosine monophosphate (cAMP) production, contributing to the increased cAMP production seen during opioid dependence and withdrawal. Thus, although we agree with previous investigators about the importance of NMDA receptors, we hypothesize that mGluRs also play a critical role in the contribution of excitatory amino acids to opioid tolerance and dependence.

Just as the nature of the pain experience can be affected by many factors, both physiologic and psychological, so can the effectiveness of opioid analgesia. Of the many possibilities, three factors are presented in this commentary in response to the preceding Focus article of Miaskowski and Levine. First, two previous studies reporting male-female differences in opioid consumption found such differences to occur only prior to age 60 to 65, at female menopause, suggesting that sex hormonal status should be considered in studies assessing the efficacy of opioid treatment. Second, given that sex and sex hormonal status have been shown to relate to both human and animal physiologic responses to stress and the likelihood that these responses affect nociceptive mechanisms, it is important to further explore these differences in order to optimize pain intervention strategies. Finally, it is encouraged that researchers strive to incorporate chronobiologic and sex hormonal considerations in future animal studies in an effort to more closely model clinical phenomena in exploring biobehavioral responses to stress, pain, and pain-relieving treatment modalities.

Recent cellular models of opioid tolerance and dependence have incorporated the idea that excitatory amino acid systems may have an important role in these phenomena. Fundytus and Coderre have developed a model that suggests a prominent role for metabotropic glutamate receptors in the initiation and the development of opioid tolerance and dependence. This Commentary briefly reviews Fundytus and Coderre's model of tolerance and dependence, offering comparisons and contrasts with the model of Mao, Price, and Mayer, which suggests a central role for N-methyl-D-aspartate receptors. Strengths and weaknesses of these models are discussed, as well as potential revisions that may lead to a more complete model of these phenomena.

Recent evidence suggests that one of the factors that may influence the assessment and management of pain is a person's gender. However, only a limited amount of information exists on gender differences in responses to analgesic medications. Based on a review of the available literature published between 1966 and 1998, we suggest that opioids are better analgesics for women. The information in this paper comes predominantly from several studies on the use of patient-controlled analgesia for the management of postoperative pain. Additional information comes from our recent work that demonstrated a sexual dimorphism in oral surgery patients' responses to three different opioid analgesics that share the property of acting as agonists at the kappa-opioid receptor. The paper concludes with a discussion of the major recommendations for future research regarding the gender biology of pain.

This Commentary evaluates several observations and hypotheses made by Fundytus and Coderre: (1) Initial treatment with high doses of μ-opioid agonists decrease phosphatidlylinositol (PI) hydrolysis, while (2) chronic treatment increases PI hydrolysis to near control levels via increased activity of type I metabotropic glutamate receptors (mGluRs) and/or δ-opioid receptors. (3) The resulting inositol 1,4,5-trisphosphate-mediated increase in protein kinase C then phosphorylates a μ-opioid coupled G-protein, leading to a desensitization of μ-opioid receptors; phosphorylates N-methyl-D-aspartate (NMDA) receptor-associated Ca²⁺ channels, resulting in a release of these channels from an Mg²⁺ block; and increases Ca²⁺/calmodulin-dependent protein kinase, which produces additional phosphorylation of μ-opioid coupled G-protein, leading to further desensitization of μ-opioid receptors. (4) A role for type II/III mGluRs in opioid dependence occurs from desensitization of these receptors, which allows 3′,5′-cyclic adenosine monophosphate to remain at levels high enough to produce withdrawal symptoms. (5) Second messenger systems interact. We then review some of the observations with which a model of opioid tolerance should be consistent. Finally, we review a model for opioid tolerance that we recently proposed.