Pain
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Neuropathic pain is associated with substantial healthcare costs. However, cost-of-illness studies of small fiber neuropathy (SFN) are scarce. Our aim was to estimate the healthcare, patient and family, and productivity costs of patients with SFN in the Netherlands from a healthcare and societal perspective. ⋯ At the patient level, the average annual SFN healthcare and societal cost of SFN was €3614 (95% confidence interval [CI] €3171-€4072) and €17,871 (95% CI €14,395-€21,480). At the SFN population level, the average healthcare costs were €29.8 (CI €26.4-€34.2) million, and on a societal level, these were €147.7 (CI 120.5-176.3) million. Severe pain was associated with significant lower Qol and higher depression scores, higher healthcare, patient and family, and productivity costs ( P < 0.001).
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Nerve injury-induced aberrant changes in gene expression in spinal dorsal horn neurons are critical for the genesis of neuropathic pain. N6-methyladenine (m 6 A) modification of DNA represents an additional layer of gene regulation. Here, we report that peripheral nerve injury significantly decreased the level of m 6 A-specific DNA methyltransferase 1 ( N6amt1 ) in dorsal horn neurons. ⋯ Rescuing the decrease in N6amt1 reversed the loss of m 6 A at the promoter for inwardly rectifying potassium channel subfamily J member 16 ( Kcnj16 ), mitigating the nerve injury-induced upregulation of Kcnj16 expression in the dorsal horn and alleviating neuropathic pain hypersensitivities. Conversely, mimicking the downregulation of N6amt1 in naive mice erased DNA m 6 A at the Kcnj16 promoter, elevated Kcnj16 expression, and led to neuropathic pain-like behaviors. Therefore, decreased N6amt1 caused by NR2F6 is required for neuropathic pain, likely through its regulation of m 6 A-controlled KCNJ16 in dorsal horn neurons, suggesting that DNA m 6 A modification may be a potential new target for analgesic and treatment strategies.
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Neuropathic pain is a critical source of comorbidity following spinal cord injury (SCI) that can be exacerbated by immune-mediated pathologies in the central and peripheral nervous systems. In this article, we investigate whether drug-free, biodegradable, poly(lactide- co -glycolide) (PLG) nanoparticle treatment mitigates the development of post-SCI neuropathic pain in female mice. Our results show that acute treatment with PLG nanoparticles following thoracic SCI significantly reduces tactile and cold hypersensitivity scores in a durable fashion. ⋯ Altered central neuropathic pain mechanisms during this period are limited to reduced innate immune cell cytokine expression. However, in the chronic phase of SCI, nanoparticle treatment induces changes in both central and peripheral neuropathic pain signaling, driving reductions in cytokine production and other immune-relevant markers. This research suggests that drug-free PLG nanoparticles reprogram peripheral proalgesic pathways subacutely after SCI to reduce neuropathic pain outcomes and improve chronic central pain signaling.
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Sex-related exacerbation of injury-induced mechanical hypersensitivity in GAD67 haplodeficient mice.
Decreased GABA levels in injury-induced loss of spinal inhibition are still under intense interest and debate. Here, we show that GAD67 haplodeficient mice exhibited a prolonged injury-induced mechanical hypersensitivity in postoperative, inflammatory, and neuropathic pain models. In line with this, we found that loss of 1 copy of the GAD67-encoding gene Gad1 causes a significant decrease in GABA contents in spinal GABAergic neuronal profiles. ⋯ Remarkably, all these phenotypes were more pronounced in GAD67 haplodeficient females. These mice had significantly much lower amount of spinal GABA content, exhibited an exacerbated pain phenotype during the second phase of the formalin test, developed a longer lasting mechanical hypersensitivity in the chronic constriction injury of the sciatic nerve model, and were unresponsive to the pain relief effect of the GABA-transaminase inhibitor phenylethylidenehydrazine. Our study provides strong evidence for a role of GABA levels in the modulation of injury-induced mechanical pain and suggests a potential role of the GABAergic system in the prevalence of some painful diseases among females.
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Although regulation of nociceptive processes in the dorsal horn by deep brain structures has long been established, the role of cortical networks in pain regulation is minimally explored. The medial prefrontal cortex (mPFC) is a key brain area in pain processing that receives ascending nociceptive input and exerts top-down control of pain sensation. We have shown critical changes in mPFC synaptic function during neuropathic pain, controlled by endocannabinoid (eCB) signaling. ⋯ Spared nerve injury reduced the mechanical threshold to induce action potential firing of dorsal horn wide-dynamic-range neurons, but this was reversed in rats by WIN in the chronic phase of SNI and by mPFC injection of AM4113 in the early phase of SNI. Elevated dorsal root ganglion neuronal activity after injury was also diminished in rats by mPFC injection of AM4113, potentially by reducing antidromic activity and subsequent neuronal inflammation. These findings suggest that depending on the phase of the pain condition, both blocking and activating CB1 receptors in the mPFC can regulate descending control of pain and affect both dorsal horn neurons and peripheral sensory neurons, contributing to changes in pain sensitivity.