Pain
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Injury to peripheral nerves often produces non-physiological, long-lasting spontaneous pain, hyperalgesia and allodynia that are refractory to standard treatment and often insensitive to opioids, such as morphine. Recent studies demonstrate spinal glial activation and increased proinflammatory cytokines in animal models of neuropathic pain. When these data are considered together, a unifying hypothesis emerges which implicates a role of central neuroimmune processes in the etiology of neuronal and behavioral hypersensitivity. ⋯ These findings directly correlated with the ability of propentofylline to inhibit glial activation and enhanced spinal proinflammatory cytokines following peripheral nerve injury. These findings along with our earlier observations of an anti-allodynic activity of propentofylline using the identical animal model of mononeuropathy supports the concept that modulation of glial and neuroimmune activation may be potential therapeutic targets to treat or prevent neuropathic pain. Further, restoration of the analgesic activity of morphine by propentofylline treatment suggests that increased glial activity and proinflammatory cytokine responses may account for the decreased analgesic efficacy of morphine observed in the treatment of neuropathic pain.
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Comparative Study
Impairment of interleukin-1 (IL-1) signaling reduces basal pain sensitivity in mice: genetic, pharmacological and developmental aspects.
The cytokine interleukin-1 (IL-1) has been implicated in modulation of pain perception under various inflammatory conditions. The present study examined the hypothesis that IL-1 signaling is also involved in pain sensitivity under normal, non-inflammatory states, using three mouse models of impaired IL-1 signaling: targeted deletion of the IL-1 receptor type I or the IL-1 receptor accessory protein, and transgenic over-expression of IL-1 receptor antagonist within the brain and spinal cord. Thermal and mechanical pain sensitivity was assessed using the paw-flick, hot-plate, and von Frey tests. ⋯ To differentiate between developmental vs. on-going effects of IL-1, mice were chronically treated with IL-1 receptor antagonist (IL-1ra) via osmotic micropumps, either in adulthood or prenatally (throughout the last 2 weeks of gestation). Adult mice that were treated with IL-1ra either in adulthood or in utero, displayed lower pain sensitivity, similar to mice with impaired IL-1 signaling. These findings suggest that basal pain sensitivity is genetically, developmentally and tonically influenced by IL-1 signaling.
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Activation of either B1 or B2 bradykinin receptors by kinins released from damaged tissues contributes to the development and maintenance of inflammatory hyperalgesia. Whereas B2 agonists activate sensory neurones directly, B1 agonists were thought only to have indirect actions on sensory neurones. The recent discovery of constitutive B1 receptor expression in the rat nervous system lead us to re-investigate the role of neuronal B1 receptors in inflammatory hyperalgesia. ⋯ The B1 agonist, desArg9BK, did not affect paw withdrawal thresholds in nai;ve rats following intraplantar administration into the paw, whilst intrathecal administration elicited mechanical hyperalgesia. However, after Freund's complete adjuvant-induced inflammation, desArg9BK caused a marked mechanical hyperalgesia, by either route, of the contralateral, uninflamed hindpaw, correlating with the observed contralateral and ipsilateral increases in receptor levels. Our results suggest a functional role for B1 receptors expressed both in the periphery and in the spinal cord, in mechanical hyperalgesia during inflammation.