Analgesic effect of highly reversible ω-conotoxin FVIA on N type Ca2+ channels

<p>Abstract</p> <p>Background</p> <p>N-type Ca²⁺channels (Ca_v2.2) play an important role in the transmission of pain signals to the central nervous system. ω-Conotoxin (CTx)-MVIIA, also called ziconotide (Prialt^®), effectively alleviates pain, without causing addiction, by blocking the pores of these channels. Unfortunately, CTx-MVIIA has a narrow therapeutic window and produces serious side effects due to the poor reversibility of its binding to the channel. It would thus be desirable to identify new analgesic blockers with binding characteristics that lead to fewer adverse side effects.</p> <p>Results</p> <p>Here we identify a new CTx, FVIA, from the Korean <it>Conus Fulmen </it>and describe its effects on pain responses and blood pressure. The inhibitory effect of CTx-FVIA on N-type Ca²⁺channel currents was dose-dependent and similar to that of CTx-MVIIA. However, the two conopeptides exhibited markedly different degrees of reversibility after block. CTx-FVIA effectively and dose-dependently reduced nociceptive behavior in the formalin test and in neuropathic pain models, and reduced mechanical and thermal allodynia in the tail nerve injury rat model. CTx-FVIA (10 ng) also showed significant analgesic effects on writhing in mouse neurotransmitter- and cytokine-induced pain models, though it had no effect on acute thermal pain and interferon-γ induced pain. Interestingly, although both CTx-FVIA and CTx-MVIIA depressed arterial blood pressure immediately after administration, pressure recovered faster and to a greater degree after CTx-FVIA administration.</p> <p>Conclusions</p> <p>The analgesic potency of CTx-FVIA and its greater reversibility could represent advantages over CTx-MVIIA for the treatment of refractory pain and contribute to the design of an analgesic with high potency and low side effects.</p

Adipose Tissue-Derived Stem Cells Alleviate Cold Allodynia in a Rat Spinal Nerve Ligation Model of Neuropathic Pain

Neuropathic pain caused by lesions or nervous system dysfunction is a neuroimmune disease with limited therapeutic options. Adipose tissue-derived stem cells (ASCs) are multipotent mesenchymal stem cells with potent immunosuppressive properties, and their use as novel cell-based therapeutics have been proposed in many immune diseases. However, the analgesic effect and efficacy of ASCs to treat neuropathic pain remain unclear. This study, thus, investigated whether ASCs or ASC-derived culture medium can relieve neuropathic pain behaviors (i.e., mechanical and cold allodynia) in a rat model with L5 spinal nerve ligation. Intrathecal injection of ASCs significantly reduced cold allodynia, but not mechanical allodynia. Importantly, cold allodynia was completely reversed in rats with repeated injections of ASCs. In contrast, intrathecal injection of ASC-derived culture medium or retro-orbital injection of ASCs had no effect on neuropathic pain behaviors. These results suggest a novel and alternative therapeutic application of ASCs to target specific neuropathic pain behaviors

Formaldehyde-Induced Aggravation of Pruritus and Dermatitis Is Associated with the Elevated Expression of Th1 Cytokines in a Rat Model of Atopic Dermatitis.

Atopic dermatitis is a complex disease of heterogeneous pathogenesis, in particular, genetic predisposition, environmental triggers, and their interactions. Indoor air pollution, increasing with urbanization, plays a role as environmental risk factor in the development of AD. However, we still lack a detailed picture of the role of air pollution in the development of the disease. Here, we examined the effect of formaldehyde (FA) exposure on the manifestation of atopic dermatitis and the underlying molecular mechanism in naive rats and in a rat model of atopic dermatitis (AD) produced by neonatal capsaicin treatment. The AD and naive rats were exposed to 0.8 ppm FA, 1.2 ppm FA, or fresh air (Air) for 6 weeks (2 hours/day and 5 days/week). So, six groups, namely the 1.2 FA-AD, 0.8 FA-AD, Air-AD, 1.2 FA-naive, 0.8 FA-naive and Air-naive groups, were established. Pruritus and dermatitis, two major symptoms of atopic dermatitis, were evaluated every week for 6 weeks. After that, samples of the blood, the skin and the thymus were collected from the 1.2 FA-AD, the Air-AD, the 1.2 FA-naive and the Air-naive groups. Serum IgE levels were quantified with ELISA, and mRNA expression levels of inflammatory cytokines from extracts of the skin and the thymus were calculated with qRT-PCR. The dermatitis and pruritus significantly worsened in 1.2 FA-AD group, but not in 0.8 FA-AD, compared to the Air-AD animals, whereas FA didn't induce any symptoms in naive rats. Consistently, the levels of serum IgE were significantly higher in 1.2 FA-AD than in air-AD, however, there was no significant difference following FA exposure in naive animals. In the skin, mRNA expression levels of Th1 cytokines such as TNF-α and IL-1β were significantly higher in the 1.2 FA-AD rats compared to the air-AD rats, whereas mRNA expression levels of Th2 cytokines (IL-4, IL-5, IL-13), IL-17A and TSLP were significantly higher in 1.2 FA-naive group than in the Air-naive group. These results suggested that 1.2 ppm of FA penetrated the injured skin barrier, and exacerbated Th1 responses and serum IgE level in the AD rats so that dermatitis and pruritus were aggravated, while the elevated expression of Th2 cytokines by 1.2 ppm of FA in naive rats was probably insufficient for clinical manifestation. In conclusion, in a rat model of atopic dermatitis, exposure to 1.2 ppm of FA aggravated pruritus and skin inflammation, which was associated with the elevated expression of Th1 cytokines

Elevation of expression of skin Th2 cytokines, IL-17A and TSLP by FA exposure in naive rats.

<p>The 1.2 FA-naive group shows significantly higher expression of Th2 cytokines such as IL-4, -5, and -13 (A~C), IL-17A (D) and TSLP (E) compared to the Air-naive group. However, the 1.2 FA-AD group does not show any significant difference in the expression level of Th2 cytokines (A~C), IL-17A (D) and TSLP (E) compared to the Air-AD group (A~E). Expression level of some of Th2 cytokines such as IL-4 (A) and IL-13 (B) is significantly higher in the Air-AD group than in the FA-naive group. Abbreviations; 1.2: 1.2 ppm, FA: formaldehyde, AD: atopic dermatitis, Air: fresh air. *<i>p<</i>0.05.</p

Aggravation of scratch and dermatitis, and increase in serum IgE level by FA exposure in AD rats.

<p>Photographs show dermatitis in the 5^th week. (A). The 1.2 FA-AD, but not 0.8 FA-AD, group shows significantly more severe scratch behavior (B) and dermatitis (D), compared to the Air-AD group. The 1.2 FA-AD group also shows significantly higher serum IgE level compared to the Air-AD group (F). However, there is no change in the symptoms (C & E) and serum IgE level (F) in naive groups. There is no significant difference in body weight among the six groups (G). Abbreviations; 1.2: 1.2 ppm, 0.8: 0.8 ppm, FA: formaldehyde, AD: atopic dermatitis, Air: fresh air. *<i>p<</i>0.05, ***<i>p<</i>0.001.</p

No change in expression of Th2 and Th1 cytokines by FA exposure in the thymus.

<p>No significant change in Th2 cytokines such as IL-4, IL-5 and IL-13, TSLP, IL-17A (A), and Th1 cytokines including TNF-α and IL-1β (B) in the thymus following exposure to 1.2 ppm of FA in both AD and naive rats. Abbreviations; 1.2: 1.2 ppm, FA: formaldehyde, AD: atopic dermatitis, Air: fresh air.</p

Natural Killer Cells Degenerate Intact Sensory Afferents following Nerve Injury

International audienceSensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity. This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves