Abstract
Morphine-induced hyperalgesia (MIH) is a severe adverse effect accompanying repeated morphine treatment, causing a paradoxical decrease in nociceptive threshold. Previous reports associated MIH with a decreased expression of the Cl− extruder KCC2 in the superficial dorsal horn (SDH) of the spinal cord, weakening spinal GABAA/glycine-mediated postsynaptic inhibition. Here, we tested whether the administration of small molecules enhancing KCC2, CLP257 and its pro-drug CLP290, may counteract MIH. MIH was typically expressed within 6–8 days of morphine treatment. Morphine-treated rats exhibited decreased withdrawal threshold to mechanical stimulation and increased vocalizing behavior to subcutaneous injections. Chloride extrusion was impaired in SDH neurons measured as a depolarizing shift in EGABA under Cl− load. Delivering CLP257 to spinal cord slices obtained from morphine-treated rats was sufficient to restore Cl− extrusion capacity in SDH neurons. In vivo co-treatment with morphine and oral CLP290 prevented membrane KCC2 downregulation in SDH neurons. Concurrently, co-treatment with CLP290 significantly mitigated MIH and acute administration of CLP257 in established MIH restored normal nociceptive behavior. Our data indicate that enhancing KCC2 activity is a viable therapeutic approach for counteracting MIH. Chloride extrusion enhancers may represent an effective co-adjuvant therapy to improve morphine analgesia by preventing and reversing MIH.
Highlights
Paradoxical morphine-induced hyperalgesia (MIH) is a form of nociceptive sensitization in which subjects exposed to morphine treatment develop a paradoxical increased pain sensitivity or exacerbate pre-existing pain[1, 2]
No differences were observed in the I-V curve slopes (CTR: 20.1 ± 1.6 pA/mV; MOR: 20.7 ± 1.6 pA/mV; MOR + CLP257: 21.8 ± 2.2 pA/mV; n = 6 per group; One-way analysis of variance (ANOVA), P = 0.8)
We found that oral administration of CLP290 given concurrently with morphine (10 mg/kg subcutaneous - s.c. - twice a day) for 7 days prevented the downregulation of KCC2 in the superficial dorsal horn (SDH) (Fig. 2a and b)
Summary
Paradoxical morphine-induced hyperalgesia (MIH) is a form of nociceptive sensitization in which subjects exposed to morphine treatment develop a paradoxical increased pain sensitivity or exacerbate pre-existing pain[1, 2]. In contrast to MIH, tolerance was associated with platelet-derived growth factor receptor-β receptor signaling[7] and a recent report identifies microglial pannexin-1 overexpression as a distinct substrate for withdrawal to morphine[8]. We recently identified a microglia-to-neuron pathway in the spinal dorsal horn which causes MIH, without affecting morphine tolerance[9]. The molecular cascade involved a P2X4 receptor-dependent release of brain-derived neurotrophic factor (BDNF) from activated microglia which, in turn, down-regulated the K+-Cl− co-transporter KCC2 in nociceptive neurons of the superficial dorsal horn (SDH)[9]. Our data demonstrate that restoring KCC2 expression on the membrane of SDH neurons and reversing impaired Cl− extrusion capacity in morphine-treated rats can effectively counteract MIH
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