Pain
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Sensitization to continued nociceptive stimulation is supposed to be involved in the development of chronic pain at several levels of the CNS, but experimental studies investigating the perceptual dynamics of sensitization in humans are rare, and the diagnostic validity of experimental pain models is not known. The present study used a tonic heat paradigm to assess early sensitization (15-100 s) to experimental pain in 30 chronic pain patients (15 musculoskeletal/back pain, 15 headache) and 23 healthy controls. Change in pain sensation during prolonged stimulation was measured by a dual sensitization method which combines subjective ratings and behavioural responses in an indirect psychophysical protocol protected against response bias. ⋯ Discriminant analysis demonstrated good sensitivity and specificity of individual sensitization measures for distinguishing pain syndromes, particularly in combination with pain thresholds. The results are in accordance with current models of spinal plasticity contributing to pathological pain states. They argue for the diagnostic value of psychophysical measures of sensitization.
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According to the cognitive-behavioral model of chronic pain, patient beliefs about their chronic pain influence their behavioral and psychological functioning. Previous correlational and longitudinal studies have supported this hypothesis. However, since previous research has relied almost exclusively on patient self-report to assess both beliefs and functioning, shared method variance may explain some of the relationships found. ⋯ Measures of patient beliefs were more strongly associated with self-report measures of pain behaviors and functioning than with spouse and observer ratings of patient pain behaviors. However, significant associations between patient beliefs and both spouse- and observer-reported frequency of patient pain behaviors were found. These findings argue for the generalizability of the relationship found between patient beliefs and patient behaviors across assessment domains, and for the continued application of the cognitive-behavioral model to the understanding of patient adjustment to chronic pain.
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Although it is well known that cannabinoids produce antinociception in acute pain models, there is less information on the ability of cannabinoids to alleviate hyperalgesia. In the present study, we determined whether cannabinoids attenuated the development of hyperalgesia produced by intraplantar injection of capsaicin in rats. In normal, untreated animals, intraplantar injection of 10 microg capsaicin produces nocifensive behavior (elevation of the injected paw) suggestive of pain, an increase in the frequency of withdrawal from punctate mechanical stimuli applied to the paw (mechanical hyperalgesia) and a decrease in the latency of withdrawal from noxious heat (heat hyperalgesia). ⋯ Furthermore, these doses of WIN 55,212-2 had no effect on basal withdrawal responses to heat in animals that did not receive capsaicin. The inactive enantiomer WIN 55,212-3 did not alter the development of capsaicin-evoked pain or hyperalgesia. These data suggest that low doses of cannabinoids, which do not produce analgesia or impair motor function, attenuate chemogenic pain and possess antihyperalgesic properties.
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Two classes of neurons with distinct responses to opioids have been identified in the rostral ventromedial medulla (RVM), a region with a well-documented role in nociceptive modulation. 'Off-cells' are activated, indirectly, by opioids, and are likely to exert a net inhibitory effect on nociceptive processing. 'On-cells' are directly inhibited by opioids, and there is evidence that these neurons can, under various conditions, facilitate nociception. We showed previously that excitatory amino acid (EAA) neurotransmission is crucial to the nocifensor reflex-related on-cell burst, but plays little role in maintaining the ongoing activity of off-cells. The aim of the present study was to determine whether EAA transmission contributes to the activation of off-cells and the concomitant behavioral antinociception that follow systemic opioid administration. ⋯ Opioid inhibition of the TF was also reduced, although baseline TF latency was unaffected, by RVM kynurenate. EAA-mediated activation of off-cells, thus has an important role in opioid analgesia. The present observations underscore the importance of excitatory interactions among opioid-sensitive nociceptive modulatory circuits for systemic morphine analgesia, suggesting that such interactions are a critical factor in the synergistic relationships which have been demonstrated among these sites.
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The present study was designed to evaluate the oral efficacy and bioavailability of ketamine. Antinociceptive efficacy was determined with the rat formalin test and oral bioavailability by the measurement of plasma and brain concentrations of ketamine and its major metabolite, norketamine. Oral ketamine in a dose range from 30 to 180 mg/kg or saline was given prior to intraplantar formalin and the flinching behavior was measured. ⋯ Competition binding assays for the [3H]MK-801-labeled non-competitive site of the N-methyl-D-aspartate receptor (NMDA) receptor revealed that both norketamine and ketamine displaced [3H]MK-801 at low micromolar concentrations with Ki values of 2.5 and 0.3 mM in the forebrain, and 4.2 and 1.0 mM in the spinal cord, respectively. Spinal norketamine was approximately equipotent to ketamine in producing antinociceptive effects during phase 2 of the formalin test. Thus, norketamine appears to contribute to the antinociceptive effects of oral ketamine through its NMDA receptor antagonist activity.