Articles: hyperalgesia.
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Nature neuroscience · Feb 2013
Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl⁻ homeostasis.
A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opiates. We found that hyperalgesia-inducing treatment with morphine resulted in downregulation of the K(+)-Cl(-) co-transporter KCC2, impairing Cl(-) homeostasis in rat spinal lamina l neurons. Restoring the anion equilibrium potential reversed the morphine-induced hyperalgesia without affecting tolerance. ⋯ Gene-targeted mice in which Bdnf was deleted from microglia did not develop hyperalgesia to morphine. However, neither morphine antinociception nor tolerance was affected in these mice. Our findings dissociate morphine-induced hyperalgesia from tolerance and suggest the microglia-to-neuron P2X4-BDNF-KCC2 pathway as a therapeutic target for preventing hyperalgesia without affecting morphine analgesia.
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At present, effective drug for treatment of neuropathic pain is still lacking. Recent studies have shown that the ligands of translocator protein (TSPO, 18 kDa), a peripheral receptor for benzodiazepine, modulate inflammatory pain. Here, we report that TSPO was upregulated in astrocytes and microglia in the ipsilateral spinal dorsal horn of rats following L5 spinal nerve ligation (L5 SNL), lasting until the vanishing of the behavioral signs of neuropathic pain (∼50 d). ⋯ Interestingly, TSPO expression returned to control levels or decreased substantially, when neuropathic pain healed naturally or was reversed by Ro5-4864, suggesting that the role of TSPO upregulation might be to promote recovery from the neurological disorder. Finally, the neuropathic pain and the upregulation of TSPO by L5 SNL were prevented by pharmacological blockage of Toll-like receptor 4 (TLR4). These data suggested that TSPO might be a novel therapeutic target for the treatment of neuropathic pain.
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Various studies have demonstrated the role of the nitric oxide (NO)/cGMP pathway in pain processing. Our group has also shown that this system participates in opioid-induced antinociception during peripheral inflammation. We have previously observed that inflammation mobilizes an endogenous opioidergic system to control hyperalgesia. ⋯ Zaprinast (200μg/paw) or l-arginine (400μg/paw) did not produce an antinociceptive effect in the contralateral paw, indicating local action. In addition, at the same dose that was able to modify carrageenan-induced hyperalgesia, neither zaprinast nor l-arginine modified PGE(2) (2μg) injection-induced hyperalgesia of the rat paw. Taken together, these results indicate that the l-arginine/NO/cGMP pathway functions as an endogenous modulator of peripheral inflammatory hyperalgesia.
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Neuropathic pain results from lesions or diseases affecting the somatosensory system. The management of patients with chronic neuropathic pain remains a challenge. Several studies support the crucial role of neuroactive steroids in the modulation of pain. ⋯ The chronic administration of progesterone significantly reduced the behavioral scores of cold- and mechano-allodynia and heat hyperalgesia but single dose of progesterone did not have any effect on behavioral scores of neuropathic pain. Our data indicate that the early chronic administration of progesterone prevents the development of neuropathic pain but its acute injection does not change the expression of neuropathic pain. These results suggest that progesterone could be considered as a new approach for management of neuropathic pain.
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Inflammation is a major factor shaping outcome during the early, acute phase of traumatic spinal cord injury (SCI). It is known that pro-inflammatory signaling within the injured spinal cord drives pathological alterations in neurosensory processing and shapes functional outcome early after injury. However, it is unclear whether inflammation persists into the chronic phase of injury or shapes sensory processing long after injury. ⋯ We found that 28 d treatment of chronically injured rats with the dual COX/5-LOX inhibitor licofelone elevated levels of endogenous anti-oxidant and anti-inflammatory metabolites within the lesion site. Furthermore, licofelone treatment reduced hypersensitivity of hindpaws to mechanical, but not thermal, stimulation, indicating that mechanical sensitivity is modulated by pro-inflammatory signaling in the chronic phase of injury. Together, these findings provide novel evidence of inflammation and oxidative stress within spinal cord tissue far into the chronic phase of SCI, and demonstrate a role for inflammatory modulation of mechanical sensitivity in the chronic phase of injury.