Pain
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Patients with temporomandibular disorder (TMD) perform poorly in neuropsychological tests of cognitive function. These deficits might be related to dysfunction in brain networks that support pain and cognition, due to the impact of chronic pain and its related emotional processes on cognitive ability. We therefore tested whether patients with TMD perform poorly in cognitive and emotion tasks and whether they had abnormal task-evoked brain activity. ⋯ These findings suggest that the slow behavioral responses in idiopathic TMD may be due to attenuated, slower, and/or unsynchronized recruitment of attention/cognition processing areas. These abnormalities may be due to the salience of chronic pain, which inherently requires attention. Sluggish performance in cognitive and emotional interference tasks in patients with nontraumatic temporomandibular disorder is associated with pronounced and unsynchronized task-evoked fMRI brain responses.
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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.
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It was previously reported that in 5 patients with small-fiber neuropathy, neuropathic pain, and hyperalgesia, application of a single, brief electrical stimulus to the skin could give rise to 2 afferent impulses in a C-nociceptor fiber. These double spikes, which are attributed to unidirectional conduction failure at branch points in the terminal arborisation, provide a possible mechanism for hyperalgesia. We here report that similar multiple spikes are regularly observed in 3 rat models of neuropathic pain: nerve crush, nerve suture, and chronic constriction injury. ⋯ Whereas only double spikes had previously been described in patients, in these more extensive recordings from rats we found that triple spikes could also be observed after a single electrical stimulus. The results strengthen the suggestion that multiple spiking, because of impaired conduction in the terminal branches of nociceptors, may contribute to hyperalgesia in patients with neuropathic pain. Double and triple spikes in c-nociceptors, caused by impaired conduction in terminal branches, may be an important cause of hyperalgesia in patients with neuropathic pain.