Enhancing KCC2 function counteracts morphine-induced hyperalgesia



Last updated:

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.

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 pain1, 2. The phenomenon has received increasing attention in clinical settings where it is often referred to in terms of diffuse pain sensation or allodynia in areas unrelated to the pain site for which the morphine treatment was prescribed2,3,4. The overall increase in pain sensitivity diminishes morphine analgesia thus limiting the long-term use of morphine in chronic pain patients. Importantly, MIH has clinical features clearly distinct from tolerance and withdrawal3. For example, while increasing morphine doses alleviates tolerance, the same approach was found ineffective or even counterproductive in targeting MIH5, 6.

Recent advances have helped unravel the molecular and neuronal mechanisms underlying MIH. Although some investigators have referred to MIH in association with morphine tolerance or withdrawal, it is now well accepted that they are sustained by distinct biological processes. For example, in contrast to MIH, tolerance was associated with platelet-derived growth factor receptor-β receptor signaling7 and a recent report identifies microglial pannexin-1 overexpression as a distinct substrate for withdrawal to morphine8.

We recently identified a microglia-to-neuron pathway in the spinal dorsal horn which specifically causes MIH, without affecting morphine tolerance9. Interestingly, the uncovered molecular pathway recapitulates the mechanistic sequelae observed in nerve-injury models10, suggesting a commonality of mechanisms between MIH and neuropathic pain9,