Pain
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Tumor necrosis factor-alpha (TNF-α) is a key proinflammatory cytokine. It is generally believed that TNF-α exerts its effects primarily via TNF receptor subtype-1 (TNFR1). We investigated the distinct roles of TNFR1 and TNFR2 in spinal cord synaptic transmission and inflammatory pain. ⋯ Our findings support a central role of TNF-α in regulating synaptic plasticity (central sensitization) and inflammatory pain via both TNFR1 and TNFR2. Our data also uncover a unique role of TNFR2 in mediating early-phase inflammatory pain. TNF-α is shown to play a critical role in regulating spinal cord synaptic plasticity and central sensitization, and TNFR1 and TNFR2 play a distinct role in regulating different phases of inflammatory pain.
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This study analyzed the relationship between the density of intraepidermal nerve fibers (IENF) and the characteristics of either nociceptive laser-evoked potentials (LEPs) or contact heat-evoked potentials (CHEPs) in patients with painful sensory polyneuropathy with the aim to determine which parameters of LEPs and CHEPs more reliably reflect IENF loss. A total of 96 patients and 35 healthy volunteers took part in the study. Based on clinical examination, nerve conduction tests, and quantitative sensory testing, we identified 52 patients with small-fiber neuropathy (SFN), 40 with mixed (small-fiber and large-fiber) neuropathy (MFN), and 4 who were excluded from the analysis because of no evidence of involvement of small fibers. ⋯ SFN patients were characterized by abnormal EPs and slightly decreased but morphologically abnormal IENF. MFN patients were characterized by frequently absent LEPs and CHEPs and a rather severe IENF loss. The correlation between nociceptive evoked potentials (laser-evoked potentials and contact heat-evoked potentials) and skin biopsy aids in the diagnosis of painful neuropathies.
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Gangliosides are abundant in neural tissue and play important roles in cell-cell adhesion, signal transduction, and cell differentiation. Gangliosides are divided into 4 groups: asialo-, a-, b-, and c-series gangliosides, based on their biosynthetic pathway. St8sia1 knockout mice, which lack b- and c-series gangliosides, exhibit altered nociceptive responses. ⋯ Thus, the antinociceptive effects of sialidase and the nociceptive effects of GT1b indicated that endogenous gangliosides are involved in nociceptive responses. These results suggest that gangliosides play important roles in nociceptive responses originating in peripheral nociceptor endings. Ganglioside GT1b induced extracellular glutamate to accumulate in subdermal tissues, thereafter activating glutamate receptors, which in turn resulted in hyperalgesia and nociception.
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Comparative Study
A novel mechanism of inhibition of high-voltage activated calcium channels by α-conotoxins contributes to relief of nerve injury-induced neuropathic pain.
α-Conotoxins that are thought to act as antagonists of nicotinic acetylcholine receptors (nAChRs) containing α3-subunits are efficacious in several preclinical models of chronic pain. Potent interactions of Vc1.1 with other targets have suggested that the pain-relieving actions of α-conotoxins might be mediated by either α9α10 nAChRs or a novel GABA(B) receptor-mediated inhibition of N-type calcium channels. Here we establish that three α-conotoxins, Vc1.1, AuIB and MII have distinct selectivity profiles for these three potential targets. ⋯ However, MII, a potent α3β2 nAChR antagonist but inactive on α9α10 and α3β4 nAChRs and GABA(B)/Ca(2+) channels, was demonstrated to have short-acting anti-allodynic action. This suggests that α3β2 nAChRs may also contribute to reversal of allodynia. Together, these findings suggest that inhibition of α9α10 nAChR is neither necessary nor sufficient for relief of allodynia and establish that α-conotoxins selective for GABA(B) receptor-dependent inhibition of N-type Ca(2+) channels relieve allodynia, and could therefore be developed to manage chronic pain.
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Proteinase-activated receptor-4 (PAR(4)) is a G-protein-coupled receptor activated by serine proteinases released during tissue repair and inflammation. We have previously shown that PAR(4) activation sensitises articular primary afferents leading to joint pain. This study examined whether mast cells contribute to this PAR(4)-induced sensitisation and consequent heightened pain behaviour. ⋯ These effects were blocked by pretreatment with cromolyn. These data reveal that PAR(4) is expressed on synovial mast cells and the activation of PAR(4) has a pronociceptive effect that is dependent on mast cell activation. Proteinase-activated receptor-4 is expressed on synovial mast cells, and the activation of Proteinase-activated receptor-4 has a pronociceptive effect that is dependent on mast cell activation.