Articles: hyperalgesia.
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Oxaliplatin, a platinum-based chemotherapeutic agent, is widely used to treat colorectal cancer, but it induces peripheral neuropathy as a serious dose-limiting side effect. Recently, thrombomodulin alfa, a recombinant human soluble thrombomodulin, was reported to prevent oxaliplatin-induced peripheral neuropathy in a clinical phase 2 study. Here we conducted preclinical pharmacology studies. ⋯ On the other hand, thrombomodulin alfa did not affect the anti-cancer activity of oxaliplatin on human colon cancer cell lines or mice transplanted with HCT116 cells. These results indicate that thrombomodulin alfa prevents sensory symptoms of oxaliplatin-induced peripheral neuropathy without affecting the anti-tumor activity of oxaliplatin. Therefore, thrombomodulin alfa is a promising drug to prevent the symptoms of oxaliplatin-induced peripheral neuropathy.
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J. Pharmacol. Exp. Ther. · Aug 2020
Chronic Morphine-Induced Changes in Signaling at the A3 Adenosine Receptor Contribute to Morphine-Induced Hyperalgesia, Tolerance, and Withdrawal.
Treating chronic pain by using opioids, such as morphine, is hampered by the development of opioid-induced hyperalgesia (OIH; increased pain sensitivity), antinociceptive tolerance, and withdrawal, which can contribute to dependence and abuse. In the central nervous system, the purine nucleoside adenosine has been implicated in beneficial and detrimental actions of morphine, but the extent of their interaction remains poorly understood. Here, we demonstrate that morphine-induced OIH and antinociceptive tolerance in rats is associated with a twofold increase in adenosine kinase (ADK) expression in the dorsal horn of the spinal cord. ⋯ SIGNIFICANCE STATEMENT: The development of hyperalgesia and antinociceptive tolerance during prolonged opioid use are noteworthy opioid-induced adverse effects that reduce opioid efficacy for treating chronic pain and increase the risk of dependence and abuse. We report that in rodents, these adverse effects are due to reduced adenosine signaling at the A3AR, resulting in NOD-like receptor pyrin domain-containing 3-interleukin-1β neuroinflammation in spinal cord. These effects are attenuated by A3AR agonists, suggesting that A3AR may be a target for therapeutic intervention with selective A3AR agonist as opioid adjuncts.
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Ubrogepant, a small-molecule calcitonin gene-related peptide receptor antagonist, was recently approved as an oral medication for the acute treatment of migraine. This study aimed to determine whether ubrogepant shows efficacy in a preclinical model of migraine-like pain and whether repeated oral administration of ubrogepant induces latent sensitization relevant to medication overuse headache in rats. ⋯ Both ubrogepant and sumatriptan demonstrated efficacy as acute medications for stress- and nitric oxide donor-evoked cephalic allodynia in a preclinical model of medication overuse headache, consistent with their clinical efficacy in the acute treatment of migraine. However, in contrast to sumatriptan, repeated treatment with ubrogepant did not induce cutaneous allodynia or latent sensitization. These studies suggest ubrogepant may offer an effective acute treatment of migraine without risk of medication overuse headache.Trial Registration Number: Not applicable.
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Physical disuse could lead to a state of chronic pain typified by complex regional pain syndrome type I due to fear of pain through movement (kinesiophobia) or inappropriate resting procedures. However, the mechanisms by which physical disuse is associated with acute/chronic pain and other pathological signs remain unresolved. We have previously reported that inflammatory signs, contractures, disuse muscle atrophy, spontaneous pain-like behaviors, and chronic widespread mechanical hyperalgesia based on central plasticity occurred after 2 weeks of cast immobilization in chronic post-cast pain (CPCP) rat model. ⋯ Furthermore, we demonstrated tactile allodynia using an optogenetic method in a transgenic rat line (W-TChR2V4), cold allodynia using the acetone test, and activation of dorsal horn neurons in the chronic phase associated with chronic mechanical hyperalgesia using c-Fos immunofluorescence. In addition, we showed that nociceptive signals in the acute phase are involved in chronic pathological pain-like behaviors by studying the effects of sciatic nerve block. Thus, we conclude that physical disuse contributes to dystrophy-like changes, spontaneous pain-like behavior, and chronic widespread pathological pain-like behaviors in CPCP rats after 2 weeks of cast immobilization.
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Medication overuse is a significant issue that complicates the treatment of headache disorders. The most effective medications for the acute treatment of migraine all have the capacity to induce medication overuse headache (MOH). Novel acute migraine-specific treatments are being developed. However, because the mechanism(s) underlying medication overuse headache are not well understood, it is difficult to predict whether any particular acute medication will induce MOH in susceptible individuals. LY573144 (lasmiditan), a 5-HT1F receptor agonist, has recently been shown to be effective in the acute treatment of migraine in phase 3 trials. The aim of this study is to determine whether frequent administration of lasmiditan induces behaviors consistent with MOH in a pre-clinical rat model. ⋯ In a pre-clinical rat model of MOH, oral lasmiditan, like sumatriptan, induced acute transient cutaneous allodynia in the periorbital and hindpaw regions that after resolution could be re-evoked by putative migraine triggers. These results suggest that lasmiditan has the capacity to induce MOH through persistent latent peripheral and central sensitization mechanisms.