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Objective: Despite the high prevalence, mild traumatic brain injury (mTBI)‐induced chronic headache and cognitive deficits are poorly understood and lack effective treatments. Low‐dose interleukin‐2 (LD‐IL‐2) treatment soon after mTBI or overexpressing IL‐2 in brain astrocytes prior to injury protects mice from developing post‐traumatic headache (PTH)‐related behaviors and cognitive decline. The present study addresses a clinically relevant knowledge gap: whether LD‐IL‐2 treatment long after the initial injury is still effective for chronic PTH and cognitive deficits. Methods: mTBI was induced by a noninvasive closed‐head weight drop method. LD‐IL‐2 was administered 4–6 weeks post‐mTBI to assess its effects on chronic PTH‐related facial mechanical hypersensitivity as well as mTBI‐induced impairment in novel object recognition and object location tests. Endogenous regulatory T (Treg) cells were depleted to investigate the mechanism of action of LD‐IL‐2. Results: Delayed LD‐IL‐2 treatment abolished chronic PTH‐related behaviors. It also completely reversed mTBI‐induced cognitive impairment in both male and female mice. Treg cell depletion not only prolonged PTH‐related behaviors but also abolished the effects of LD‐IL‐2. Interestingly, LD‐IL‐2 treatment significantly increased the number of Treg cells in dura but not in brain tissues. Interpretation: These results suggest that the beneficial effects of LD‐IL‐2 treatment are mediated through the expansion of meningeal Treg cells. Collectively, our study identifies Treg as a cellular target and LD‐IL‐2 as a promising therapy for both chronic PTH and mTBI‐induced cognitive impairment for both males and females, with a wide therapeutic time window and the potential of reducing polypharmacy in mTBI treatment. ANN NEUROL 2024;96:508–525 [ABSTRACT FROM AUTHOR]

Inhibitory synapses play key roles in the modulatory circuitry that regulates pain signaling and generation of migraine headache. A rare, dominant form of this common disease, familial hemiplegic migraine type 1 (FHM1), arises from missense mutations in the pore-forming [[alpha].sub.1A] subunit of P/Q-type [Ca.sup.2+] channels. These channels are normally vital for presynaptic [Ca.sup.2+] entry and neurotransmitter release at many central synapses, raising questions about effects of FHM1 mutations on neuronal [Ca.sup.2+] influx and inhibitory and excitatory neurotransmission. We have expressed the four original FHM1 mutant channels in hippocampal neurons from [[alpha].sub.1A] knockout mice. Whole-cell recordings indicated that FHM1 mutant channels were less effective than wild-type channels in their ability to conduct P/Q-type current, but not generally different from wild type in voltage-dependent channel gating. [Ca.sup.2+] influx triggered by action potential waveforms was also diminished. In keeping with decreased channel activity, FHM1 mutant channels were correspondingly impaired in supporting the P/Q-type component of inhibitory neurotransmission. When expressed in wild-type inhibitory neurons, FHM1 mutant channels reduced the contribution of P/Q-type channels to GABAergic synaptic currents, consistent with a competition of mutant and endogenous channels for P/Q-specific slots. In all cases, N-type channels took up the burden of supporting transmission and homeostatic mechanisms maintained overall synaptic strength. The shift to reliance on N-type channels greatly increased the susceptibility to G protein-coupled modulation of neurotransmission, studied with the GAB[A.sub.B] agonist baclofen. Thus, mutant-expressing synapses might be weakened in a heightened state of neuromodulation like that provoked by triggers of migraine such as stress. action potential waveform | inhibitory hippocampal neuron

Moderate to intense pain can only be produced through the release of tachykinins from primary afferent pain-sensing receptors, according to research into the behavioural response to painful stimuli of mice in which the preprotachykinin A gene, which encodes substance P and a related tachykinin, is disrupted. It was established that tachykinins are released by polymodal nociceptive afferents. They are vital neurotransmitters for the transmission and production of moderate to intense pain messages across modalities.

Abstract Background Migraine and other headache disorders affect a large percentage of the population and cause debilitating pain. Activation and sensitization of the trigeminal primary afferent neurons innervating the dura and cerebral vessels is a crucial step in the “headache circuit”. Many dural afferent neurons respond to algesic and inflammatory agents. Given the clear role of the transient receptor potential (TRP) family of channels in both sensing chemical stimulants and mediating inflammatory pain, we investigated the expression of TRP channels in dural afferent neurons. Methods We used two fluorescent tracers to retrogradely label dural afferent neurons in adult mice and quantified the abundance of peptidergic and non-peptidergic neuron populations using calcitonin gene-related peptide immunoreactivity (CGRP-ir) and isolectin B4 (IB4) binding as markers, respectively. Using immunohistochemistry, we compared the expression of TRPV1 and TRPA1 channels in dural afferent neurons with the expression in total trigeminal ganglion (TG) neurons. To examine the distribution of TRPM8 channels, we labeled dural afferent neurons in mice expressing farnesylated enhanced green fluorescent protein (EGFPf) from a TRPM8 locus. We used nearest-neighbor measurement to predict the spatial association between dural afferent neurons and neurons expressing TRPA1 or TRPM8 channels in the TG. Results and conclusions We report that the size of dural afferent neurons is significantly larger than that of total TG neurons and facial skin afferents. Approximately 40% of dural afferent neurons exhibit IB4 binding. Surprisingly, the percentage of dural afferent neurons containing CGRP-ir is significantly lower than those of total TG neurons and facial skin afferents. Both TRPV1 and TRPA1 channels are expressed in dural afferent neurons. Furthermore, nearest-neighbor measurement indicates that TRPA1-expressing neurons are clustered around a subset of dural afferent neurons. Interestingly, TRPM8-expressing neurons are virtually absent in the dural afferent population, nor do these neurons cluster around dural afferent neurons. Taken together, our results suggest that TRPV1 and TRPA1 but not TRPM8 channels likely contribute to the excitation of dural afferent neurons and the subsequent activation of the headache circuit. These results provide an anatomical basis for understanding further the functional significance of TRP channels in headache pathophysiology.