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Review
. 1999 Jul 6;96(14):7731-6.
doi: 10.1073/pnas.96.14.7731.

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

D J Mayer  1 , J Mao, J Holt, D D Price
Affiliations
Review

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

D J Mayer et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Figure 1
Figure 1
Effect of benzamide on morphine tolerance. Tolerance to the antinociceptive effect of morphine developed in rats treated with 20 μg of morphine for 7 days. Coadministration of 20 μg of morphine with 200 or 400 nmol (not 100 nmol) benzamide for 7 days reliably attenuated the development of tolerance. Neither baseline tail-flick latency nor the response to a single injection of 20 μg of morphine changed after repeated saline treatment for seven days. ∗∗, P < 0.01, as compared with that of day 1 in each corresponding group. Neither repeated benzamide (400 nmol) treatment alone nor a single injection of 20 of μg morphine on day 8 (the 20*/0 group) affected the degree of tolerance as compared with the saline group. MPAE%, percent of maximal possible antinociceptive effect.
Figure 2
Figure 2
Effect of benzamide on incidence of dark neurons. Coadministration of 20 μg of morphine with benzamide (100–400 nmol) for 7 days reliably prevented the increase in dark neurons. Neither repeated benzamide (400 nmol) treatment alone nor a single injection of 20 μg of morphine on day 8 (the 20*/0 group) affected the occurrence of dark neuron as compared with the saline group. ∗∗, P < 0.01, as compared with each of the rest groups.
Figure 3
Figure 3
Effect of nicotinamide and 3-aminobenzamide on morphine tolerance. Coadministration of 20 μg of morphine with either 200 nmol 3-aminobenzamide or 1 μmol niacinamide (nicotinamide) for 7 days reliably attenuated the development of tolerance. ∗∗, P < 0.01, as compared with that of day 1 in the same group.
Figure 4
Figure 4
Effect of nicotinamide and 3-aminobenzamide on incidence of dark neurons. Coadministration of 20 μg of morphine with either 200 nmol 3-aminobenzamide or 1 μmol niacinamide (nicotinamide) for 7 days also reliably prevented the increase in dark neurons. a, P < 0.05; b, P < 0.01, as compared with the MSO4 + saline group.
Figure 5
Figure 5
A proposed model for the excitotoxic formation of dark neurons in the dorsal horn of the spinal cord from peripheral nerve injury or repeated morphine administration. Excessive excitation of the NMDA receptor and subsequent influx of Ca2+ occurs either directly by glutamate release from primary afferent input (CCI model) or indirectly by activation of μ-opioid receptors (repeated opiate administration). Activation of the μ-opioid receptor results in indirect NMDA receptor activation by initiating a second-messenger PKC translocation to the membrane(16) This PKC translocation activates the NMDA receptor by removal of the Mg2+ blockade(17). The removal of the Mg2+ blockade from the NMDA receptor allows for an increased influx of Ca2+. The influx of Ca2+, via direct or indirect activation of the NMDA receptor, has several effects (5). It activates either a separate pool of PKC (PKC2) or much greater amounts of the original pool of PKC1. This second pool of PKC may be translocated directly to the membrane, modifying various excitatory amino acid or other receptors. It also may function as a transcription factor, resulting in the production of more PKC (PKC3), which can result in uncoupling of the μ-opioid receptor from its associated G protein. Another effect of the influx of Ca2+ is that it activates NO synthase, which increases the production of NO. In addition, the influx of Ca2+ results in the production of superoxide from mitochondria. The simultaneous generation of these two molecules favors the production of peroxynitrite (ONOO−), a very potent initiator of DNA strand breakage, which, in turn, initiates the production of the nuclear repair enzyme, PARS. Pronounced activation of PARS can result in cell dysfunction and eventually cell death because of inhibition of mitochondrial respiration and depletion of cellular energy stores, which in turn may lead to the formation of dark neurons, perhaps by way of programmed cell death. PKCx, various pools of protein kinase C; GPro, heterotrimeric guanine nucleotide binding protein; NOS, nitric oxide synthase.
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