Pain
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Although the administration of opioids is the most effective treatment for pain, their efficacy is limited by the development of tolerance. The midbrain periaqueductal gray matter (PAG) participates in opioid analgesia and tolerance. Microinjection of morphine into PAG produces antinociception, probably through neurons in the rostral ventromedial medulla (RVM), namely through the activation of off-cells, which inhibit nociception, and the inhibition of on-cells, which facilitate nociception. ⋯ In contrast to saline-pretreated rats, PAG microinjection of morphine in tolerant animals did not change the baseline activity of off- or on-cells, did not prevent the off-cell pause or the on-cell activation upon tail heating, and did not lengthen the tail flick latency. However, microinjection of kainic acid into the PAG (1) caused off-cells to become continuously active and on-cells to become silent, and (2) prevented the tail flick, i.e. exactly what morphine did before tolerance developed. These results demonstrate a correspondence between neuronal and behavioral measures of tolerance to PAG opioid administration, and suggest that tolerance is mediated by a change in opioid-sensitive neurons within the PAG.
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Anatomical studies demonstrate the presence of glutamate receptors on unmyelinated axons in peripheral cutaneous nerves. Pharmacological studies show that intraplantar injection of glutamate or glutamate agonists in the glabrous skin results in nociceptive behaviors. The present study describes a novel in vitro skin-nerve preparation using the glabrous skin from the rat hindpaw. ⋯ Exposure of A delta or C fibers to glutamate did not result in a decrease in von Frey thresholds. These data provide a physiological basis for the nociceptive behaviors that arise following intraplantar injection of glutamate or glutamate agonists. Furthermore, demonstration of glutamate-induced excitation and heat sensitization of nociceptors indicates that local or topical administration of glutamate receptor antagonists may have therapeutic potential for the treatment of pain.
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Evidence from animal models and studies of human sensory nerves demonstrate that tetrodotoxin (TTX)-resistant Na(+) channels are present in sensory neurons and might play an important role in pain conduction and chronic pain. Recent investigations suggest that TTX-resistant Na(+) channels in the peripheral nervous system are less sensitive to local anesthetics than TTX-sensitive Na(+) channels. To test the effects of the clinically used local anesthetics lidocaine and bupivacaine on TTX-resistant action potentials (APs) in sensory neurons, we performed electrophysiological experiments on small dorsal root ganglion (DRG) neurons from young rats. ⋯ Time to peak and duration of TTX-resistant APs were prolonged by local anesthetics. Trains of APs could be elicited in some neurons by long-lasting current injections, and the half-maximal concentrations needed to suppress these trains were 30 microM lidocaine or 10 microM bupivacaine. We suggest that the reduction in firing frequency at low concentrations of local anesthetic may explain the phenomenon of paresthesia when sensory information is gradually suppressed during spinal anesthesia.
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Randomized Controlled Trial Clinical Trial
Expectations of analgesia do not affect spinal nociceptive R-III reflex activity: an experimental study into the mechanism of placebo-induced analgesia.
The purpose of this study was to investigate whether placebo analgesia is mediated by the release of beta-endorphin. In addition to subjective pain reports, we included an objective physiological parameter of nociception reflected by the opioid sensitive nociceptive R-III reflex. Placebo consisted of strong suggestions of pain relief and an intravenous injection of saline. ⋯ Consistently, the antagonizing effects of naloxone were negligible. A subgroup analysis of those who did show a placebo response as indicated on the VAS did not support the supposition that beta-endorphin is released due to placebo suggestion. It is suggested that intensified stimuli and a more effective procedure to induce placebo analgesia (e.g. conditioning) may produce a proper placebo effect.