Pain
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The mesopontine tegmental anesthesia area (MPTA) is a focal brainstem locus which, when exposed to GABAergic agents, induces brain-state transitioning from wakefulness to unconsciousness. Correspondingly, MPTA lesions render animals relatively insensitive to GABAergic anesthetics delivered systemically. Using chemogenetics, we recently identified a neuronal subpopulation within the MPTA whose excitation induces this same pro-anesthetic effect. ⋯ We conclude that GABAAδ-Rs are the primary molecular target of GABAergic anesthetics in the MPTA. Immunolabeling revealed that this GABAA-R isoform is expressed exclusively by a distinct subpopulation of MPTA "δ-cells" that reside in close apposition to effector neurons. This suggests that during wakefulness, δ-cells serve as inhibitory interneurons which, when silenced by GABAergic agents, disinhibit (excite) the effector-neurons, triggering transition to unconsciousness.
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Temporomandibular disorder (TMD) is the most prevalent painful condition in the craniofacial area. Recent studies have suggested that external or intrinsic trauma to the temporomandibular joint (TMJ) is associated with the onset of painful TMD in patients. Here, we investigated the effects of TMJ trauma through forced-mouth opening (FMO) in mice to determine pain behaviors and peripheral sensitization of trigeminal nociceptors in both sexes. ⋯ Forced-mouth opening also increased Ca2+ responses evoked by cold, heat, and capsaicin stimuli, which was not different between the sexes. In retrogradely labeled trigeminal TMJ afferents, FMO induced an increase in small-sized neuronal proportions with increased colocalization with calcitonin gene-related peptides and transient receptor potential vanilloid subtype 1, which was modestly sex dependent. These results suggest that TMJ injury leads to persistent posttraumatic hyperalgesia associated with peripheral sensitization of trigeminal nociceptors with distinct sex dependency.
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The mechanism causing cold pain in humans is unresolved. Animal data suggest a nonredundant contribution to cold pain for transient receptor potential channels TRPM8 and TRPA1 for detection and voltage-gated sodium channels NaV1.7 and NaV1.8 for conduction at these temperatures. We established an intradermal injection-based cold pain model, which allows pharmacologically addressing molecular targets at the site of cooling. ⋯ Pain induced by 3°C intradermal fluid was not reduced to a relevant extent by any of the 4 antagonists alone or by the quadruple combination. However, the temperature threshold for cold pain appeared shifted by the inhibition of TRPA1, TRPM8, and NaV1.7 and to a lesser extent by NaV1.8 inhibition, 4-fold inhibition decreased the threshold by 5.8°C. Further mechanisms contributing to human cold pain need to be considered.
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Previous preclinical and translational studies suggest that tissue trauma related to bony fracture and intervertebral disk disruption initiates the formation of pronociceptive antibodies that support chronic musculoskeletal pain conditions. This study tested this hypothesis in the monosodium iodoacetate (MIA) mouse model of osteoarthritis (OA) and extended the findings using OA patient samples. Monosodium iodoacetate was injected unilaterally into the knees of male and female wild-type (WT) and muMT mice (lacking B cells) to induce articular cartilage damage. ⋯ Similarly, intra-articular injection of IgM from patients with OA was pronociceptive in muMT MIA mice and control subject IgM had no effect. Monosodium iodoacetate-injected joints demonstrate elevated levels of complement component 5a (C5a) and C5a receptor blockade using intra-articular PMX-53-reduced sensitization. These data suggest that MIA-treated mice and patients with OA generate pronociceptive antibodies, and further support the pronociceptive autoimmunity hypothesis for the transition from tissue injury to chronic musculoskeletal pain.