Their findings suggest this is caused by the activation of nerve cell receptors called NR2A-NMDA, and that opioids that are able to counteract this effect, such as methadone, may be promising therapeutic candidates for alleviating pain in those with fibromyalgia.
Results were reported in the study “NR2A-NMDA receptor blockade reverses the lack of morphine analgesia without affecting chronic pain status in fibromyalgia-like mouse model,” which was published in the Journal of Pharmacology and Experimental Therapeutics.
Opioids, chemical compounds that include pain relievers, analgesics, and illegal drugs, have limited effectiveness to alleviate neuropathic pain — a type of pain caused by damage or disease that affects the nervous system.
One classical example is the poor effectiveness of morphine — a potent opioid used for medical purposes — at alleviating chronic pain in people with fibromyalgia. However, why morphine and other opioids fail to alleviate pain among those with fibromyalgia is still not fully understood by scientists.
To pinpoint the molecular mechanisms underlying opioid inactivity in fibromyalgia, particularly morphine, researchers in Japan created a mouse model of fibromyalgia-like pain, in which the disease was induced by exposing animals to intermittent cold stress (ICS).
In these animals, chronic pain is generalized, affects mainly females, and is not reversed by treatment with morphine, mirroring the condition in humans.
Using this model, the researchers first investigated the relationship between chronic pain and morphine inactivity in the brain, and then focused on exploring the molecular mechanisms underlying morphine’s reduced analgesic effect.
They found that hyperalgesia — extreme sensitivity to pain — was independent of the lack of brain response to morphine, because in mice lacking type 1 lysophosphatidic acid (LPA1) that did not experience chronic pain, morphine continued to be ineffective.
Of note, LPA1 is a receptor that mediates widespread pain in animal models of fibromyalgia, and other disorders associated with chronic pain. Genetically modified animals that are unable to produce this receptor are also unable to activate the signaling cascades that trigger widespread pain.
“As the lack of morphine analgesia also remained unchanged in mice treated (…) with pregabalin, which abolished the hyperalgesia, it is evident that lack of morphine analgesia and hyperalgesia in the ICS model have independent mechanisms,” the investigators wrote.
Importantly, they discovered that the analgesic activity of morphine could be restored if mice were genetically engineered to lack NR2A-containing NMDA receptor, a receptor found at the surface of nerve cells (neurons) that is involved in the processing of pain. Of note, NR2A is a specific subunit of NMDA receptors.
They also showed that mice injected in the brain with inhibitors of NR2A (e.g. (R)-CPP) regained sensitivity to morphine, as did those treated with a NMDA receptor inhibitor (dextromethorphan), which does not have pain-relieving effects.
In addition, treatment with methadone, an opioid that blocks the activity of NMDA receptors in the brain, also increased sensitivity to morphine.
“All these results suggest that chronic pain status and lack of morphine analgesia are independent to each other, and the lack of morphine analgesia is mediated by an activation of NR2A-NMDA receptor system,” the researchers wrote.
“As the present study demonstrated that the ICS-induced pain was suppressed by methadone, which is reported to have significant side effects, the development of hybrid compounds with… NMDA receptor antagonist [blocking] activities, but less adverse effects would be promising for pain suppression in FM [fibromyalgia] patients” they said.
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