Endogenous opioids released during non-nociceptive environmental stress induce latent pain sensitization Via a NMDA-dependent process.

UNLABELLED: Although stress induces analgesia, there is evidence that stressful events may exacerbate pain syndromes. Here, we studied the effects of 1 to 3 prestressful events (days 0, 2, and 7), such as non-nociceptive environmental stress, on inflammatory hyperalgesia induced by a carrageenan injection (day 14) in 1 rat hind paw. Changes in nociceptive threshold were evaluated by the paw pressure vocalization test. The higher the number of stress sessions presented to the rats, the greater was the inflammatory hyperalgesia. Blockade of opioid receptors by naltrexone before each stress inhibited stress-induced analgesia and suppressed the exaggerated inflammatory hyperalgesia. Stressed versus nonstressed animals could be discriminated by their response to a fentanyl ultra-low dose (fULD), that produced hyperalgesia or analgesia, respectively. This pharmacological test permitted the prediction of the pain vulnerability level of prestressed rats because fULD analgesic or hyperalgesic indices were positively correlated with inflammatory hyperalgesic indices (r(2) = .84). In prestressed rats, fULD-induced hyperalgesia and the exaggerated inflammatory hyperalgesia were prevented NMDA receptor antagonists. This study provides some preclinical evidence that pain intensity is not only the result of nociceptive input level but is also dependent on the individual history, especially prior life stress events associated with endogenous opioid release. PERSPECTIVE: Based on these preclinical data, it would be of clinical interest to evaluate whether prior stressful events may also affect further pain sensation in humans. Moreover, this preclinical model could be a good tool for evaluating new therapeutic strategies for relieving pain hypersensitivity.

A single nitrous oxide (N2O) exposure leads to persistent alleviation of neuropathic pain in rats.

UNLABELLED: Using the rat chronic constriction injury (CCI) pain model, we evaluated whether nitrous oxide (N2O), a gas shown to have potent anti-hyperalgesic properties, may alleviate neuropathic pain. Mechanical nociceptive threshold was estimated using the paw pressure vocalization test. Thermal allodynia was challenged by measuring the struggle latency by immersion of the hind paw in a 10 degrees C water bath. A single 50% N2O exposure for 1 hour, 15 minutes not only induced potent anti-nociception during N2O exposure but also provoked a delayed and sustained reduction (37% to 46%) of pain hypersensitivity of the injured hind paw and abolished pain hypersensitivity of the contralateral uninjured hind paw for at least 1 month. Thermal allodynia was completely prevented by a single N2O exposure. A preadministration of naltrexone, which markedly reduced acute N2O-induced anti-nociception, did not affect the persistent reduction of hyperalgesia. The administration of naltrexone in N2O-treated rats, 1 week after the gas exposure, did not induce any effect. This suggests that the long-lasting effect of N2O was not due to its prior acute analgesic effect and was independent of endogenous opioid systems. These data suggest that 50% N2O exposure could be an efficient and safe strategy for alleviating neuropathic pain in a persistent manner. PERSPECTIVE: Because a single 50% N2O exposure induced a persistent reduction of hyperalgesia-allodynia in a rat neuropathic pain model, clinical trials must be developed for evaluating the N2O effects in patients with neuropathic pain. The ability of N2O to potentiate analgesic effects of other drugs also must be evaluated.

Long-term pain vulnerability after surgery in rats: prevention by nefopam, an analgesic with antihyperalgesic properties.

BACKGROUND: Tissue damage associated with surgery often produces peripheral and central sensitization that may outlast the stimuli, leading to exaggerated postoperative pain. Paradoxically, the use of opioid analgesia, which is essential for surgical pain management may induce pain sensitization leading to enhanced postoperative pain and an increased risk of developing chronic pain. We studied whether a surgical incision in the rat hindpaw may favor the development of long-term pain vulnerability by estimating hyperalgesia induced by an inflammatory stimulation of the unlesioned contralateral hindpaw 3 wk later. We also evaluated the ability of nefopam, an analgesic drug commonly used in postoperative pain management, to prevent not only exaggerated postoperative pain but also long-term pain vulnerability. The efficacy of morphine was assessed 1 day after surgical incision. METHODS: On Day 0, a surgical plantar incision was performed in one hindpaw of rats treated or untreated with fentanyl (4 x 100 microg/kg, one injection every 15 min). Nefopam (10 mg/kg) or saline was subcutaneously injected 30 min before injury. Three weeks later, once pain measures had returned to basal values, a subsequent nociceptive stimulus, specifically intraplantar carrageenan injection, was performed to evaluate pain sensitivity in incision- and fentanyl-experienced rats. Pain was measured by the paw-pressure vocalization test and the weight bearing test. RESULTS: Surgical incision in rats induced latent and long-term pain hypersensitivity, which was manifested by exaggerated hyperalgesia on carrageenan injection. Administering fentanyl in association with the surgical incision induced exaggerated postoperative pain. When injected before incision, nefopam reduced the exaggerated postoperative pain induced by perioperative fentanyl treatment and prevented the development of long-term pain hypersensitivity. Preoperative nefopam administration also improved morphine analgesic efficacy in the context of fentanyl-induced postoperative hyperalgesia. CONCLUSIONS: Given preemptively, nefopam may be effective at improving postoperative pain management and at reducing the risk of developing postoperative chronic pain, because the drug has both analgesic and antihyperalgesic properties.