Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions

Abstract

Compelling evidence has accumulated over the last several years from our laboratory, as well as others, indicating that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. In our laboratory, chronic constriction injury of the common sciatic nerve, a rat model of neuropathic pain, has been shown to result in activation of central nervous system excitatory amino acid receptors and subsequent intracellular cascades including protein kinase C translocation and activation, nitric oxide production, and nitric oxide-activated poly(ADP ribose) synthetase activation. Similar cellular mechanisms also have been implicated in the development of tolerance to the analgesic effects of morphine. A recently observed phenomenon, the development of ''dark neurons,'' is associated with both chronic constriction injury and morphine tolerance. A site of action involved in both hyperalgesia and morphine tolerance is in the superficial laminae of the spinal cord dorsal horn. These observations suggest that hyperalgesia and morphine tolerance may be interrelated at the level of the superficial laminae of the dorsal horn by common neural substrates that interact at the level of excitatory amino acid receptor activation and subsequent intracellular events. The demonstration of interrelationships between neural mechanisms underlying hyperalgesia and morphine tolerance may lead to a better understanding of the neurobiology of these two phenomena in particular and pain in general. This knowledge may also provide a scientific basis for improved pain management with opiate analgesics.A number of studies, both from our laboratory as well as others, indicate that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. We have recently shown in a rat model of neuropathic pain that chronic constrictive injury (CCI) of the common sciatic nerve can result in activation of central nervous system excitatory amino acid receptors and subsequent intracellular cascades including protein kinase C translocation and activation, nitric oxide (NO) production, and NO-activated poly(ADP ribose) synthetase (PARS) activation. Similar cellular mechanisms also have been implicated in the development of tolerance to the analgesic effects of morphine. Of particular interest is that morphological changes in the spinal cord dorsal horn, the development of so called ''dark neurons,'' are associated with both CCI and morphine tolerance. A site of action involved in both hyperalgesia and morphine tolerance has also been shown to be in the superficial laminae of the spinal cord dorsal horn. We will first summarize recent evidence indicating central mechanisms of hyperalgesia and morphine tolerance. The main focus of this article will be on the recent development in our understanding of the involvement of PARS activation in central...

Regulation of neuronal chloride homeostasis by neuromodulators

“…1995; Mayer et al . 1999). Therefore, opioid‐induced analgesia may occur via increasing KCC2 function and strengthening inhibition in DRG neurons.…”

Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats

“…Neuronal plasticity associated with hyperalgesia and morphine tolerance has similar cellular and molecular mechanisms, suggesting predictable interactions between hyperalgesia and morphine tolerance (Mao et al, 1995;Mayer et al, 1999). The induction of pain facilitation by sustained opioid exposure contribute to the development of opioid antinociceptive tolerance, and manipulations that block enhanced pain also block antinociceptive tolerance (Ossipov et al, 2003).…”

Attenuation of Acute Morphine Withdrawal in the Neonatal Rat by the Competitive NMDA Receptor Antagonist LY235959

“…There is increasing evidence indicating that N-methyl-D-aspartate (NMDA) receptor antagonists inhibit the development of mu receptor mediated opiate dependence in the adult NO . 3 rodent, and that the NMDA receptor and its second messenger systems play pivotal roles in opiate tolerance, dependence and withdrawal (Trujillo and Akil 1991a;Inturrisi 1997;Mao 1999;Mayer et al 1999).It is not known whether these mechanisms in adults apply to infants. On the one hand, opiate dependence can be established in fetuses or infant rat pups if the dams are exposed to opiates during their pregnancy or the pups are treated directly with opiates Barr 1995, 2000;Windh et al 1995;Barr et al 1998).…”

“…There is increasing evidence indicating that N-methyl-D-aspartate (NMDA) receptor antagonists inhibit the development of mu receptor mediated opiate dependence in the adult NO . 3 rodent, and that the NMDA receptor and its second messenger systems play pivotal roles in opiate tolerance, dependence and withdrawal (Trujillo and Akil 1991a;Inturrisi 1997;Mao 1999;Mayer et al 1999).…”

“…Despite decades of research, our understanding of the mechanisms underlying opiate physical dependence and withdrawal is still very limited (Mayer et al 1999;Trujillo 1999) and multiple mechanisms may operate in these processes (Thorat et al 1994). There is increasing evidence indicating that N-methyl-D-aspartate (NMDA) receptor antagonists inhibit the development of mu receptor mediated opiate dependence in the adult rodent, and that the NMDA receptor and its second messenger systems play pivotal roles in opiate tolerance, dependence and withdrawal (Trujillo and Akil 1991a;Inturrisi 1997;Mao 1999;Mayer et al 1999).…”