4.1. Opioid Tolerance and Neuropathic Pain
As discussed above, NMDA receptor-mediated cellular and intracellular changes occur within the rat's spinal cord following repeated exposure to opioids. Similar cellular and intracellular changes have been observed at the spinal cord level in animal models of neuropathic pain. Several lines of evidence suggest that these NMDA receptor-mediated changes are the neural basis of spinal cord neuroplastic changes responsible for the behavioral manifestations of both opioid tolerance and hyperalgesia (a sign of neuropathic pain) (62). Because these changes occur at the same spinal cord loci, it is possible that interactions may occur between NMDA receptor-mediated changes following repeated opioid exposure and neuropathic pain; that is, opioids may exacerbate hyperalgesia associated with at least certain types of neuropathic pain and lead to hyperalgesia even in the absence of pre-existing neuropathic pain. A corollary of this is that neuroplastic changes from neuropathic pain may, under some circumstances, reduce the response to opioid analgesics.
Because NMDA receptors are critical for the development of both hyperalgesia and ^-opioid tolerance, conditions such as peripheral nerve injury leading to the development of hyperalgesia have been shown to decrease the antinociceptive effectiveness of opioids in the absence of repeated exposure to opioids (86-88). The reduced opioid analgesia mimics pharmacological tolerance, thereby significantly hampering the ability of opioids to treat neuropathic pain. Conversely, because repeated exposure to opioids, a process leading to the development of pharmacological tolerance, involves activation of NMDA receptors, NMDA receptor-mediated hyperalgesia does, indeed, occur in association with the development of ^-opioid tolerance (44,89,90), further reducing the effectiveness of opioid analgesics. In this regard, repeated opioid administration would not only result in the development of tolerance (a desensitization process) and also lead to activation of the pain facilitatory process (a sensitization process). Thus, interactions between opioid and NMDA receptors may play a significant role in neuroplastic changes following repeated opioid exposure and neuropathic pain.
The interactions between neuroplastic changes following repeated opioid exposure and neuropathic pain have clear clinical implications. For example, it is a common clinical experience that opioids are less effective and often unreliable for treating neuropathic pain such as that resulting from peripheral nerve injury. It is conceivable that the diversity of clinical response patterns to opioid therapy in neuropathic pain patients may result from various degrees of CNS neuroplastic changes initiated by conditions of neuropathic pain. Such neuroplastic changes may underlie the development of neuropathic pain syndromes and also result in a reduction of the antinociceptive effects of opioids.
On the other hand, repeated treatment with opioids could lead to changes within the spinal cord through interactions between opioid and NMDA receptors, mimicking the condition of neuropathic pain following nerve injury. Apparently, a common factor in both directions is the activation of NMDA receptors. This concept is the basis for recommending a combined use of opioids and clinically available NMDA receptor antagonists, because these two classes of agents would complement each other in a well-balanced treatment regimen (62). Importantly, such a strategy should be integrated into treatment regimens both for managing chronic pain syndromes and preventing an evolving pain condition such as that after nerve injury (83,91).
Our understanding of the cellular and molecular mechanisms of opioid tolerance has been significantly advanced over the last decade. Evidence suggests that mechanisms of opioid tolerance have much in common with NMDA receptor-mediated neuroplastic changes that are associated with many types of substance abuse and neurological disorder. Although details of such mechanisms remain to be elaborated, it can be anticipated that studies on the NMDA receptor-mediated cellular and molecular mechanisms of opioid tolerance and their interactions with those of neuropathic pain will lead to improvement in opioid therapy for pain management.
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