TNFR2 Signaling in Hippocampal CA3 Pyramidal Neurons Recruits the Opioid and Endocannabinoid to Resolve Chronic Neuropathic Pain
Open Access DepositedTNFR2 activation in hippocampal neurons concurrently recruits β-endorphin (to engage μ-opioid receptors) and (oleoyl ACP hydrolase) OLAH-dependent lipids (to engage CB1 receptors), and the concerted action of these two pathways reinstates normal nociceptive processing. In summary, this work demonstrates that TNFR2 signaling in a discrete population of hippocampal pyramidal neurons orchestrates a two-pronged endogenous analgesic program that can resolve chronic neuropathic pain. By harnessing the brain’s own pain-suppressing peptides and lipid transmitters, TNFR2 agonism achieves long-lasting relief without the need for exogenous opioids. These findings reveal a previously unappreciated role for the hippocampus in active pain resolution and highlight TNFR2 as a promising therapeutic target. Selective activation of TNFR2, by virtue of engaging intrinsic opioid and cannabinoid pathways, could represent a safe, non-addictive treatment strategy for chronic neuropathic pain.
naltrexone abrogated TNFR2-mediated analgesia in male mice, but female mice remained largely unaffected by opioid receptor blockade, indicating that males rely more heavily on the β-endorphin pathway for TNFR2-driven pain resolution. In parallel, our data showed that TNFR2 activation engages an endocannabinoid “arm.” When we administered AM251, a selective cannabinoid 1 (CB1) receptor antagonist, it completely prevented the TNFR2 agonist from alleviating neuropathic pain in both sexes. This result indicates that intact CB1 signaling is requisite for TNFR2’s beneficial effects. Together, the opioid and endocannabinoid findings define a dual endogenous analgesic axis
Chronic neuropathic pain (CNP) arises from sustained neuroinflammation and maladaptive synaptic plasticity within the nervous system, making it a complex and challenging condition to treat. Despite its high prevalence and impact, affecting ~50 million people (over 20% of the population) in the United States, the available therapies for neuropathic pain provide inadequate relief for many patients and often carry significant side effects. There is an urgent clinical need for new approaches that can durably alleviate neuropathic pain without the drawbacks of opioid analgesics. This dissertation explores a novel strategy centered on the tumor necrosis factor (TNF) signaling pathway. In particular, we focus on TNF receptor 2 (TNFR2), a receptor with immunoregulatory and neuroprotective roles, and investigate its capacity to engage the brain’s own pain-suppressing systems to promote recovery from chronic pain.We employed a combination of genetic and pharmacological tools in a mouse model of peripheral nerve injury (chronic constriction injury, CCI) to dissect the role of TNFR2 in supraspinal pain modulation. Using a transgenic mouse line (Nex-CreERT2) to specifically delete TNFR2 in cortical and hippocampal excitatory neurons, including hippocampal cornu ammonis 3 (CA3) pyramidal cells, we investigated how the absence of neuronal TNFR2 affects the resolution of neuropathic pain. In parallel, we administered a selective TNFR2 agonist systemically to evaluate whether activating this pathway could reverse established pain behaviors. Behavioral outcomes were assessed by measuring mechanical allodynia (paw withdrawal thresholds) over time after nerve injury. Interestingly, mice lacking TNFR2 in Nex-expressing neurons failed to recover from neuropathic allodynia, in contrast to their littermate controls, demonstrating that neuronal TNFR2 is required for endogenous pain resolution. Conversely, treatment with the TNFR2 agonist markedly alleviated CNP in wild-type mice, restoring pain thresholds toward normal, but had no effect in the neuron-specific TNFR2 knockouts. These findings establish that the pain-relieving benefit of TNFR2 activation depends on the presence of TNFR2 in a specific subset of neurons, revealing a critical supraspinal site of action for this pathway. To uncover the mechanisms by which neuronal TNFR2 activation drives pain resolution, we conducted molecular and pharmacological analyses focusing on two major intrinsic analgesic systems
the endogenous opioid and endocannabinoid pathways. Transcriptomic profiling and immunohistochemical studies of the hippocampus revealed that engaging TNFR2 triggers a pronounced upregulation of proopiomelanocortin (POMC) and its peptide product β-endorphin within CA3 pyramidal neurons. β-Endorphin is a potent endogenous opioid, and its increased production suggested an “opioid arm” to the analgesic mechanism. Consistently, pharmacological blockade of μ-opioid receptors with naltrexone reversed the pain relief induced by TNFR2 activation. Notably, this effect displayed a sex difference
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