Pain
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Astrocytic PTEN regulates neuropathic pain by facilitating HMGCR-dependent cholesterol biosynthesis.
Recent studies have noted the role of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in developing neuropathic pain, but the underlying mechanisms are obscure. We found that PTEN was mainly expressed in astrocytes in the rat spinal cord and dramatically downregulated after chronic constriction injury (CCI). Intrathecal injection of a PTEN inhibitor induced pain-related behaviors in naive rats. ⋯ Finally, cholesterol replenishment attenuated CCI-induced pain and suppressed spinal glial activation. Taken together, these findings imply that spinal astrocytic PTEN plays a beneficial role in CCI-induced pain by regulating cholesterol biosynthesis, and an increased level of PTEN may accelerate cholesterol biosynthesis and reduce glial activation, thereby alleviating neuropathic pain. Recovery of PTEN or cholesterol might be an effective therapeutic strategy for neuropathic pain.
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Migraine is a complex neurovascular disorder that is one of the leading causes of disability and a reduced quality of life. Even with such a high societal impact, our understanding of the cellular and molecular mechanisms that contribute to migraine headaches is limited. To address this complex disorder, several groups have performed genome-wide association studies to elucidate migraine susceptibility genes, with many identifying transient receptor potential melastatin 8 (TRPM8), a cold-sensitive cation channel expressed in peripheral afferents innervating the trigeminovascular system, and the principal mediator of cold and cold pain associated with injury and disease. ⋯ Our results show that both evoked and spontaneous pain behaviors are dependent on both TRPM8 channels and neurons, as well as required in both acute and chronic migraine models. Moreover, inhibition of TRPM8 channels prevented acute but not established chronic migraine-like pain. These results are consistent with its association with migraine in genetic analyses and establish that TRPM8 channels are a component of the underlying mechanisms of migraine.