Pain
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Predictions which invoke evolutionary mechanisms are hard to test. Agent-based modeling in artificial life offers a way to simulate behaviors and interactions in specific physical or social environments over many generations. The outcomes have implications for understanding adaptive value of behaviors in context. ⋯ Allowing exploitation of injured agents decreased expression of pain to near zero, but altruists remained. Decreasing costs or increasing benefits of helping hardly changed its frequency, whereas increasing interaction rate between injured agents and helpers diminished the benefits to both. Agent-based modeling allows simulation of complex behaviors and environmental pressures over evolutionary time.
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Severe pain is a common and debilitating complication of metastatic bone cancer. Current analgesics provide insufficient pain relief and often lead to significant adverse effects. In models of cancer-induced bone pain, pathological sprouting of sensory fibers at the tumor-bone interface occurs concomitantly with reactive astrocytosis in the dorsal horn of the spinal cord. ⋯ Furthermore, CGRP induced ATP release in astrocytes, which was inhibited by CGRP8-37. We suggest that the peripheral increase in CGRP content observed in cancer-induced bone pain is mirrored by a central increase in the extracellular levels of CGRP. This increase in CGRP not only may facilitate glutamate-driven neuronal nociceptive signaling but also act on astrocytic CGRP receptors and lead to release of ATP.
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Below-level central neuropathic pain (CNP) affects a large proportion of spinal cord injured individuals. To better define the dynamic changes of the spinal cord neural network contributing to the development of CNP after spinal cord injury (SCI), we characterized the morphological and behavioral correlates of CNP in female C57BL/6 mice after a moderate T11 contusion SCI (50 kdyn) and the influence of moderate physical activity. Compared with sham-operated animals, injured mice developed mechanical allodynia 2 weeks post injury when tested with small-diameter von Frey hair filaments (0.16 g and 0.4 g filament), but presented hyporesponsiveness to noxious mechanical stimuli (1.4 g filament). ⋯ Analysis of IB4-labeled nonpeptidergic sensory fibers revealed no differences between experimental groups. Abnormalities in temperature sensation were not influenced by physical activity. Thus, treadmill training partially resolves signs of below-level CNP after SCI and modulates the density of CGRP-labeled fibers.
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Clinical studies show that chronic pain can spread to adjacent or even distant body regions in some patients. However, little is known about how this happens. In this study, we found that partial infraorbital nerve transection (p-IONX) in MRL/MPJ mice induced not only marked and long-lasting orofacial thermal hyperalgesia but also thermal hyperalgesia from day 3 postoperatively (PO) and tactile allodynia from day 7 PO in bilateral hind paws. ⋯ In addition, microglial activation after p-IONX transmitted caudally from the Vc in the medulla to lumber dorsal horn in a time-dependent manner. Inhibition of microglial activation by minocycline at early but not late stage after p-IONX postponed and attenuated pain sensitization in the hind paw. These results indicate that neuropathic pain after p-IONX in MRL/MPJ mice spreads from the orofacial region to distant somatic regions and that a rostral-caudal transmission of central sensitization in the spinal cord is involved in the spreading process of pain hypersensitivity.
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The rostroventral medial medulla (RVM) is part of a rapidly acting spino-bulbo-spinal loop that is activated by ascending nociceptive inputs and drives descending feedback modulation of spinal nociception. In the adult rat, the RVM can facilitate or inhibit dorsal horn neuron inputs but in young animals descending facilitation dominates. It is not known whether this early life facilitation is part of a feedback loop. ⋯ The results support the hypothesis that early life descending facilitation of spinal nociception is independent of sensory input. Since it is not altered by RVM glutamatergic receptor activation, it is likely generated by spontaneous brainstem activity. Only later in postnatal life can this descending activity be modulated by ascending nociceptive inputs in a functional spinal-bulbo-spinal loop.