Neuroimmune interactions regulating the balance between remission and relapse of pain

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Principal Investigator: Geoffroy O Laumet
Organization: MICHIGAN STATE UNIVERSITY
Fiscal Year: 2024
Award: $388,249
Funding agency: National Institute of Neurological Disorders and Stroke

Persistent pain is common and debilitating. Long after apparent remission of the pain initiated by
the primary insult, some patients experience relapse and recurrent episodes of severe pain. The
long-term goal of this project is to decipher mechanisms that regulate the balance between
remission and relapse of pain. Understanding these mechanisms will help to identify new
therapeutic strategies to prevent the transition from acute to chronic pain and reduce the use of
opioid for treatment of pain. We have developed a new mouse model to study the remission and
relapse of pain. After a primary insult (surgical incision or a short dose of chemotherapy), a short
period of pain (acute pain) is followed by remission in which pain sensitivity is absent. However,
during remission pain can be reinstated by inhibition of anti-inflammatory cytokine or opioid
receptor signaling, neither of which affect pain sensitivity in naive animals. Our preliminary data
show that interleukin (IL)-10 is permanently upregulated during remission from pain and keeps
neuroinflammation silent and upregulates δ-opioid receptor (δOR) gene expression and analgesic
effects.
This suggests that remission is a sensitized state that results from long-term neuroplasticity in
the nociceptive system, which if inhibited will trigger relapse of pain. Our long-term goal is to
switch transient remission to permanent recovery. Towards this goal, the central hypothesis of
our proposal is that persistent IL-10 signaling is necessary to prevent the relapse to pain by
keeping neuroinflammation silent and facilitating the activation of the endogenous opioid
system. Thus, we will test this hypothesis with 2 specific aims. Our first aim will test the
hypothesis that IL-10 signaling acts as a “brake” to keep neuroinflammation latent and prevents
relapse to pain. Our second aim will investigate the hypothesis that relapse is prevented
because IL-10 signaling promotes upregulation of gene expression and functional activation of
δOR in the DRG. This proposal will fill critical gaps of knowledge on the roles of neuroimmune
and immune-opioid crosstalk in chronic pain.
Because regulation of the remission and relapse of pain has not been investigated previously,
our model of pain recurrence can transform our knowledge on long lasting nociceptive plasticity
in chronic pain. Ultimately, it could transform clinical practices by treating patients in remission
to prevent the relapse of pain.

Terms: <Absence of pain sensation><Absence of sensibility to pain><Acute Pain><Affect><Analgesic Agents><Analgesic Drugs><Analgesic Preparation><Analgesics><Animals><Anodynes><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Antinociceptive Agents><Antinociceptive Drugs><Biochemistry><Biological Chemistry><CNS plasticity><CSIF><CSIF-10><Calcium><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Characteristics><Cytokine Receptors><Cytokine Synthesis Inhibitory Factor><Data><Disease remission><Dorsal Root Ganglia><Dose><Down-Regulation><Equilibrium><Event><Exhibits><FDA approved><Feels no pain><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fostering><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Genes><Goals><IL-10><IL-10 receptor><IL10><IL10A><Image><Immune><Immunes><Immunoassay><Individual><Interleukin 10 Precursor><Interleukin-10><Interleukins><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><Maintenance><Mediating><Medulla Spinalis><Modeling><Neuroimmune><Neuronal Plasticity><No sensitivity to pain><Nociception><Opiate Receptors><Opiate agonist><Opiate receptor agonist><Opiates><Opioid><Opioid Receptor><Opioid agonist><Opioid receptor agonist><Otomy><Pain><Pain Control><Pain Research><Pain Therapy><Pain management><Painful><Patients><Persistent pain><Population><Post-Operative><Postoperative><Postoperative Period><RNA Seq><RNA sequencing><RNAseq><Receptor Signaling><Recovery><Recurrence><Recurrent><Recurrent pain><Regulation><Relapse><Remission><Research><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Source><Spinal><Spinal Cord><Spinal Ganglia><Surgical incisions><System><Testing><Thinking><Transgenic Mice><Up-Regulation><Upregulation><acute to chronic pain transition><analgesia><balance><balance function><biological signal transduction><central nervous system plasticity><chemotherapy><chronic pain><chronic pain patient><chronic pain transition><clinical practice><constant pain><delta opioid receptor><dorsal horn><dorsal root ganglion><endogenous opiate><endogenous opioids><experience><flow cytophotometry><gene signatures><genetic signature><imaging><incision><innovate><innovation><innovative><insight><interleukin-10 receptor><interventional strategy><lasting pain><magnetic beads><mouse model><murine model><neural inflammation><neural plasticity><neuroinflammation><neuroinflammatory><neuropathic pain><neuroplastic><neuroplasticity><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><nociceptive><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><on-going pain><ongoing pain><pain chronification><pain killer><pain medication><pain model><pain reliever><pain sensitivity><pain treatment><painful neuropathy><painkiller><patch clamp><patient with chronic pain><pharmacologic><prevent><prevent relapse><preventing><public health relevance><relapse prevention><social role><spontaneous pain><therapeutic agent development><therapeutic development><thoughts><transcriptome sequencing><transcriptomic sequencing><transition to chronic pain><δ OR><δ ORs><δ opioid receptors><δ-OR><δ-ORs><δOR><δORs>