Understanding the mechanisms that drive transition from acute to chronic pain is essential to identify new therapeutic targets. The importance of endogenous resolution pathways acting as a "brake" to prevent development of chronic pain has been largely ignored. We examined the role of interleukin-10 (IL-10) in resolution of neuropathic pain induced by cisplatin. In search of an underlying mechanism, we studied the effect of cisplatin and IL-10 on spontaneous activity (SA) in dorsal root ganglia neurons. Cisplatin (2 mg/kg daily for 3 days) induced mechanical hypersensitivity that resolved within 3 weeks. In both sexes, resolution of mechanical hypersensitivity was delayed in Il10 mice, in WT mice treated intrathecally with neutralizing anti-IL-10 antibody, and in mice with cell-targeted deletion of IL-10R1 on advillin-positive sensory neurons. Electrophysiologically, small- to medium-sized dorsal root ganglia neurons from cisplatin-treated mice displayed an increase in the incidence of SA. Cisplatin treatment also depolarized the resting membrane potential, and decreased action potential voltage threshold and rheobase, while increasing ongoing activity at -45 mV and the amplitude of depolarizing spontaneous fluctuations. In vitro addition of IL-10 (10 ng/mL) reversed the effect of cisplatin on SA and on the depolarizing spontaneous fluctuation amplitudes, but unexpectedly had little effect on the other electrophysiological parameters affected by cisplatin. Collectively, our findings challenge the prevailing concept that IL-10 resolves pain solely by dampening neuroinflammation and demonstrate in a model of chemotherapy-induced neuropathic pain that endogenous IL-10 prevents transition to chronic pain by binding to IL-10 receptors on sensory neurons to regulate their activity.

Interleukin-10 resolves pain hypersensitivity induced by cisplatin by reversing sensory neuron hyperexcitability.

Nowadays, high epidemic obesity-triggered hypertension and diabetes seriously damage social public health. There is now a general consensus that the body’s fat content exceeding a certain threshold can lead to obesity. Calcium ion is one of the most abundant ions in the human body. A large number of studies have shown that calcium signaling could play a major role in increasing energy consumption by enhancing the metabolism and the differentiation of adipocytes and reducing food intake through regulating neuronal excitability, thereby effectively decreasing the occurrence of obesity. In this paper, we review multiple calcium signaling pathways, including the IP3 (inositol 1,4,5-trisphosphate)-Ca2+ (calcium ion) pathway, the p38-MAPK (mitogen-activated protein kinase) pathway, and the calmodulin binding pathway, which are involved in biological clock, intestinal microbial activity, and nerve excitability to regulate food intake, metabolism, and differentiation of adipocytes in mammals, resulting in the improvement of obesity.

Calcium Signaling Pathways: Key Pathways in the Regulation of Obesity.

Sensory abnormalities generated by nerve injury, peripheral neuropathy or disease are often expressed as neuropathic pain. This type of pain is frequently resistant to therapeutic intervention and may be intractable. Numerous studies have revealed the importance of enduring increases in primary afferent excitability and persistent spontaneous activity in the onset and maintenance of peripherally-induced neuropathic pain. Much of this activity results from increased activity, modulation and /or expression of voltage-gated Na+ channels and hyperpolarization-activated cyclic nucleotide–gated (HCN) channels (particularly Nav1.3, 1.7, 1.8 and 1.9 and HCN2). Expression and/or function of K+ channels is reduced. This also increases excitability, alters axonal conduction and increases neurotransmitter release from primary afferent terminals in the spinal dorsal horn. The properties of nociceptive free nerve endings may also be affected. Although A-channels (Kv1.4, 3.3, 3.4, 4.1, 4.2 and 4.3), KCNQ or M-channels (Kv7.2, 7.3, 7.4 and 7.5) and ATP-sensitive channels (Kir6.2) have been extensively studied in this regard, less information is available for other K+ channel types particularly Ca2+-activated K+ channels (KCa1.1, 2.1, 2.2, 2.3 and 3.1), Na+-activated K+ channels (KCa4.1 and 4.2) and two pore domain leak channels (K2p; TWIK related channels). This review presents the distribution, physiological role and effect of injury on K+ channels in nociceptive and non-nociceptive primary afferents and how injury-induced changes might contribute to the onset and persistence of neuropathic pain. Whilst it is established that various mediators, including cytokines and growth factors bring about injury-induced changes in DRG function and excitability, evidence presently available points to a seminal role for interleukin 1 (IL-1) in control of K+ channel function. Despite the current state of knowledge, attempts to target K+ channels for therapeutic pain management have met with very limited success. Moreover, K+ channel activators such as pinacidil, retigabine, flupirtine and diazoxide which are approved for other therapeutic applications, have not gained widespread acceptance in the area of pain management. This situation may change with the advent of personalized medicine. Identification of specific sensory abnormalities and genetic profiling of individual patients may predict therapeutic benefit of K+ channel activators.

/pdf/k-channels-in-primary-afferents-and-their-role-in-nerve-4qbpzlc5ck.pdf

K+ Channels in Primary Afferents and Their Role in Nerve Injury-Induced Pain.

MiR-30b-5p attenuates oxaliplatin-induced peripheral neuropathic pain through the voltage-gated sodium channel Nav1.6 in rats.

Inhibition of voltage-gated calcium (CaV) channels is a potential therapy for many neurological diseases including chronic pain. Neuronal CaV1/CaV2 channels are composed of α, β, γ and α2δ subunits. The β subunits of CaV channels are cytoplasmic proteins that increase the surface expression of the pore-forming α subunit of CaV. We targeted the high-affinity protein-protein interface of CaVβ's pocket within the CaVα subunit. Structure-based virtual screening of 50,000 small molecule library docked to the β subunit led to the identification of 2-(3,5-dimethylisoxazol-4-yl)-N-((4-((3-phenylpropyl)amino)quinazolin-2-yl)methyl)acetamide (IPPQ). This small molecule bound to CaVβ and inhibited its coupling with N-type voltage-gated calcium (CaV2.2) channels, leading to a reduction in CaV2.2 currents in rat dorsal root ganglion sensory neurons, decreased presynaptic localization of CaV2.2 in vivo, decreased frequency of spontaneous excitatory postsynaptic potentials and miniature excitatory postsynaptic potentials, and inhibited release of the nociceptive neurotransmitter calcitonin gene-related peptide from spinal cord. IPPQ did not target opioid receptors nor did it engage inhibitory G protein-coupled receptor signaling. IPPQ was antinociceptive in naive animals and reversed allodynia and hyperalgesia in models of acute (postsurgical) and neuropathic (spinal nerve ligation, chemotherapy- and gp120-induced peripheral neuropathy, and genome-edited neuropathy) pain. IPPQ did not cause akinesia or motor impairment, a common adverse effect of CaV2.2 targeting drugs, when injected into the brain. IPPQ, a quinazoline analog, represents a novel class of CaV2.2-targeting compounds that may serve as probes to interrogate CaVα-CaVβ function and ultimately be developed as a nonopioid therapeutic for chronic pain.

Targeting the CaVα–CaVβ interaction yields an antagonist of the N-type CaV2.2 channel with broad antinociceptive efficacy

N-type voltage-gated calcium (Cav2.2) channels are expressed in the central terminals of dorsal root ganglion (DRG) neurons, and are critical for neurotransmitter release. Cav2.2 channels are also expressed in the soma of DRG neurons, where their function remains largely unknown. Here, we showed that Cav2.2 was upregulated in the soma of uninjured L4 DRG neurons, but downregulated in those of injured L5 DRG neurons following L5 spinal nerve ligation (L5-SNL). Local application of specific Cav2.2 blockers (ω-conotoxin GVIA, 1–100 μM or ZC88, 10–1000 μM) onto L4 and 6 DRGs on the operated side, but not the contralateral side, dose-dependently reversed mechanical allodynia induced by L5-SNL. Patch clamp recordings revealed that both ω-conotoxin GVIA (1 μM) and ZC88 (10 μM) depressed hyperexcitability in L4 but not in L5 DRG neurons of L5-SNL rats. Consistent with this, knockdown of Cav2.2 in L4 DRG neurons with AAV-Cav2.2 shRNA substantially prevented L5-SNL-induced mechanical allodynia and hyperexcitability of L4 DRG neurons. Furthermore, in L5-SNL rats, interleukin-1 beta (IL-1β) and IL-10 were upregulated in L4 DRGs and L5 DRGs, respectively. Intrathecal injection of IL-1β induced mechanical allodynia and Cav2.2 upregulation in bilateral L4–6 DRGs of naive rats, whereas injection of IL-10 substantially prevented mechanical allodynia and Cav2.2 upregulation in L4 DRGs in L5-SNL rats. Finally, in cultured DRG neurons, Cav2.2 was dose-dependently upregulated by IL-1β and downregulated by IL-10. These data indicate that the upregulation of Cav2.2 in uninjured DRG neurons via IL-1β over-production contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury.

Upregulation of N-type calcium channels in the soma of uninjured dorsal root ganglion neurons contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury.

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Upregulation of N-type calcium channels in the soma of uninjured dorsal root ganglion neurons contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury.