Interleukin-6 is an inflammatory cytokine with wide-ranging biological effects. It has been widely demonstrated that neuroinflammation plays a critical role in the development of pathological pain. Recently, various pathological pain models have shown elevated expression levels of interleukin-6 and its receptor in the spinal cord and dorsal root ganglia. Additionally, the administration of interleukin-6 could cause mechanical allodynia and thermal hyperalgesia, and an intrathecal injection of anti-interleukin-6 neutralizing antibody alleviated these pain-related behaviors. These studies indicated a pivotal role of interleukin-6 in pathological pain. In this review, we summarize the recent progress in understanding the roles and mechanisms of interleukin-6 in mediating pathological pain associated with bone cancer, peripheral nerve injury, spinal cord injury, chemotherapy-induced peripheral neuropathy, complete Freund’s adjuvant injection, and carrageenan injection. Understanding and regulating interleukin-6 could be an interesting lead to novel therapeutic strategies for pathological pain.

/pdf/interleukin-6-an-emerging-regulator-of-pathological-pain-1t87av87l2.pdf

Interleukin-6: an emerging regulator of pathological pain

The tumor suppressor PTEN is a major homeostatic regulator, by virtue of its lipid phosphatase activity against phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], which downregulates the PI3K/AKT/mTOR prosurvival signaling, as well as by its protein phosphatase activity towards specific protein targets. PTEN catalytic activity is crucial to control cell growth under physiologic and pathologic situations, and it impacts not only in preventing tumor cell survival and proliferation, but also in restraining several cellular regeneration processes, such as those associated with nerve injury recovery, cardiac ischemia, or wound healing. In these conditions, inhibition of PTEN catalysis is being explored as a potentially beneficial therapeutic intervention. Here, an overview of human diseases and conditions in which PTEN inhibition could be beneficial is presented, together with an update on the current status of specific small molecule inhibitors of PTEN enzymatic activity, their use in experimental models, and their limitations as research or therapeutic drugs.

PTEN Inhibition in Human Disease Therapy

Dysregulated excitability within the spinal dorsal horn is a critical mediator of chronic pain. In the rodent nerve injury model of neuropathic pain, BDNF-mediated loss of inhibition (disinhibition) gates the potentiation of excitatory GluN2B N-methyl-d-aspartate receptor (NMDAR) responses at lamina I dorsal horn synapses. However, the centrality of this mechanism across pain states and species, as well as the molecular linker involved, remain unknown. Here, we show that KCC2-dependent disinhibition is coupled to increased GluN2B-mediated synaptic NMDAR responses in a rodent model of inflammatory pain, with an associated downregulation of the tyrosine phosphatase STEP61. The decreased activity of STEP61 is both necessary and sufficient to prime subsequent phosphorylation and potentiation of GluN2B NMDAR by BDNF at lamina I synapses. Blocking disinhibition reversed the downregulation of STEP61 as well as inflammation-mediated behavioural hypersensitivity. For the first time, we characterize GluN2B-mediated NMDAR responses at human lamina I synapses and show that a human ex vivo BDNF model of pathological pain processing downregulates KCC2 and STEP61 and upregulates phosphorylated GluN2B at dorsal horn synapses. Our results demonstrate that STEP61 is the molecular brake that is lost following KCC2-dependent disinhibition and that the decrease in STEP61 activity drives the potentiation of excitatory GluN2B NMDAR responses in rodent and human models of pathological pain. The ex vivo human BDNF model may thus form a translational bridge between rodents and humans for identification and validation of novel molecular pain targets.

/pdf/loss-of-step61-couples-disinhibition-to-n-methyl-d-aspartate-44zcpubhtg.pdf

Loss of STEP61 couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing

Hyperactivity of the glutamatergic system is involved in the development of central sensitization in the pain neuraxis, associated with allodynia and hyperalgesia observed in patients with chronic pain. Herein we study the ability of type 4 metabotropic glutamate receptors (mGlu4) to regulate spinal glutamate signaling and alleviate chronic pain. We show that mGlu4 are located both on unmyelinated C-fibers and spinal neurons terminals in the inner lamina II of the spinal cord where they inhibit glutamatergic transmission through coupling to Cav2.2 channels. Genetic deletion of mGlu4 in mice alters sensitivity to strong noxious mechanical compression and accelerates the onset of the nociceptive behavior in the inflammatory phase of the formalin test. However, responses to punctate mechanical stimulation and nocifensive responses to thermal noxious stimuli are not modified. Accordingly, pharmacological activation of mGlu4 inhibits mechanical hypersensitivity in animal models of inflammatory or neuropathic pain while leaving acute mechanical perception unchanged in naive animals. Together, these results reveal that mGlu4 is a promising new target for the treatment of chronic pain.

https://www.jneurosci.org/content/jneuro/33/48/18951.full.pdf

Alleviating Pain Hypersensitivity through Activation of Type 4 Metabotropic Glutamate Receptor

Dexmedetomidine, an imidazoline compound, is a highly selective α2-adrenoceptor agonist with sympatholytic, sedative, amnestic, and analgesic properties. In order to minimize the patients' pain and anxiety during minimally invasive spine surgery (MISS) when compared to conventional surgery under general anesthesia, an adequate conscious sedation (CS) or monitored anesthetic care (MAC) should be provided. Commonly used intravenous sedatives and hypnotics, such as midazolam and propofol, are not suitable for operations in a prone position due to undesired respiratory depression. Dexmedetomidine converges on an endogenous non-rapid eye movement (NREM) sleep-promoting pathway to exert its sedative effects. The great merit of dexmedetomidine for CS or MAC is the ability of the operator to recognize nerve damage during percutaneous endoscopic lumbar discectomy, a representative MISS. However, there are 2 shortcomings for dexmedetomidine in MISS: hypotension/bradycardia and delayed emergence. Its hypotension/bradycardiac effects can be prevented by ketamine intraoperatively. Using atipamezole (an α2-adrenoceptor antagonist) might allow doctors to control the rate of recovery from procedural sedation in the future. MAC, with other analgesics such as ketorolac and opioids, creates ideal conditions for MISS. In conclusion, dexmedetomidine provides a favorable surgical condition in patients receiving MISS in a prone position due to its unique properties of conscious sedation followed by unconscious hypnosis with analgesia. However, no respiratory depression occurs based on the dexmedetomidine-related endogenous sleep pathways involves the inhibition of the locus coeruleus in the pons, which facilitates VLPO firing in the anterior hypothalamus.

Safe Sedation and Hypnosis using Dexmedetomidine for Minimally Invasive Spine Surgery in a Prone Position

Activation of α2 adrenoceptors inhibited NMDA receptor-mediated nociceptive transmission in spinal dorsal horn of mice with inflammatory pain.

BACKGROUND: The reduction of gamma-aminobutyric acid (GABA) type A receptor-mediated inhibition has long been implicated in spinal sensitization of nociceptive responses. However, it is largely unknown which signaling cascades in spinal dorsal horn neurons are initiated by the reduced inhibition to trigger pain hypersensitivity.METHODS: GABAergic inhibition was manipulated by intrathecal application of GABA type A receptor antagonist bicuculline in intact mice or by GABA type A receptor agonist muscimol in complete Freund's adjuvant-injected mice. Immunoblotting, coimmunoprecipitation, immunohistochemistry, and behavioral tests were used to explore the signaling pathways downstream of the altered GABAergic tone.RESULTS: The study data revealed that the 61-kD isoform of striatal-enriched protein phosphatase (STEP61) was a key molecule that relayed the signals from GABAergic neurotransmission. The authors found that STEP61 was highly expressed in dorsal horn neurons. Under physiological conditions, STEP61 tonically interacted with and negatively controlled the activities of extracellular signal-regulated kinase and Src-family protein tyrosine kinases member Fyn, two critical kinases involved in spinal sensitization. Once GABAergic inhibition was impaired, STEP61 interaction with its substrates was substantially disturbed, allowing for activation of extracellular signal-regulated kinase and Fyn (n = 4 to 6). The hyperactivities of extracellular signal-regulated kinase and Fyn, along with STEP61 dysregulation, caused the tyrosine phosphorylation and synaptic accumulation of GluN2B subunit-containing N-methyl-D-aspartate subtype of glutamate receptors (n = 6), leading to GluN2B receptor-dependent pain hypersensitivity. Overexpression of wild-type STEP61 to resume its enzymatic activity significantly blocked the mechanical allodynia evoked by bicuculline and more importantly, alleviated chronic inflammatory pain (n = 6 in each group).CONCLUSION: These data identified STEP61 as a key intermediary for GABAergic inhibition to regulate pain sensitization.

GABAergic inhibition regulated pain sensitization through STEP61 signaling in spinal dorsal horn of mice.

Inhibition of protein tyrosine phosphatases in spinal dorsal horn attenuated inflammatory pain by repressing Src signaling.

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Activation of α2 adrenoceptors inhibited NMDA receptor-mediated nociceptive transmission in spinal dorsal horn of mice with inflammatory pain.

GABAergic inhibition regulated pain sensitization through STEP61 signaling in spinal dorsal horn of mice.

Inhibition of protein tyrosine phosphatases in spinal dorsal horn attenuated inflammatory pain by repressing Src signaling.