Pain
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In this preliminary study, we evaluated the effects of methylnaltrexone, a peripheral opioid-receptor antagonist, on chronic opioid-induced gut motility and transit changes in four subjects with chronic methadone-induced constipation. Subjects participated in this single blind, placebo controlled study for up to 8 days. We gave placebo the first day; for the remainder of the study, we gave intravenous methylnaltrexone (0.05-0.45 mg/kg) twice daily. ⋯ Oral-cecal transit times of Subjects 1, 3, and 4 were reduced from 150, 150 and 150 min (after placebo) to 90, 60 and 60 min (with methylnaltrexone), respectively. Our preliminary results demonstrate that low dose intravenous methylnaltrexone effectively reversed chronic methadone-induced constipation and delay in gut transit time. Thus, we anticipate that cancer patients receiving chronic opioids may also have increased sensitivity to methylnaltrexone, and that low dose methylnaltrexone may have clinical utility in managing opioid-induced constipation in chronic-pain patients.
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Perioral electrical stimuli cause inhibitory reflex responses in single motor-units (SMU) and surface electromyographic (EMG) recordings from voluntary contracted human jaw-closing muscles. Tonic experimental masseter pain has recently been shown to reduce the inhibitory reflex response in surface EMG recordings but the effect on SMU activity has not been described. In this study, motor-unit action potentials were recorded with wire electrodes inserted into the left masseter in eleven subjects. ⋯ Tonic masseter pain did not change pre-stimulus SMU firing characteristics but the mean ISI for the first post-stimulus discharge (158.2+/-9.2 ms) was significantly decreased compared to the pre-pain (175.8+/-11.3 ms, P<0.05) and post-pain conditions (172. 6+/-11.6 ms, P<0.05). The post-stimulus firing probability was significantly increased and the relative amplitude of the estimated IPSP significantly decreased during tonic masseter pain compared to pre-pain and post-pain conditions. In conclusion, this study indicates that tonic masseter pain has a net excitatory effect on the inhibitory jaw-reflexes, which could be mediated by presynaptic mechanisms on the involved motoneurons.
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The objective of this study was to investigate the central processing of dynamic mechanical allodynia in patients with mononeuropathy. Regional cerebral blood flow, as an indicator of neuronal activity, was measured with positron emission tomography. Paired comparisons were made between three different states; rest, allodynia during brushing the painful skin area, and brushing of the homologous contralateral area. ⋯ This finding is consistent with previous studies suggesting attentional modulation and a central coping strategy for known and expected painful stimuli. Involvement of the medial pain system has previously been reported in patients with mononeuropathy during ongoing spontaneous pain. This study reveals a bilateral activation of the lateral pain system as well as involvement of the medial pain system during dynamic mechanical allodynia in patients with mononeuropathy.
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Expression of bradykinin receptors was analyzed in freshly isolated dorsal root ganglion neurons of the ipsi- and contralateral segments L4/L5, L2/L3, and T12/T13 two to twenty days after unilateral injury of the adult rat sciatic nerve using gold labeled bradykinin. The number of infiltrating leucocytes was investigated by flow cytometry. Sciatic nerve injury transiently increased the proportion of neurons expressing bradykinin receptors not only in the ipsilateral ganglia L4/L5, but also in the homonymous contralateral ganglia and also bilaterally in the adjacent ganglia L2/L3. ⋯ No increase was observed prior to day ten and only in ipsilateral ganglia L4/L5, not contralaterally and not in adjacent ganglia L2/L3 and T12/T13. The experiments show that the induction of bradykinin receptors following a unilateral nerve lesion is not restricted to neurons projecting into the damaged nerve but is (i) bilateral, (ii) different in time course between injured and uninjured neurons, and (iii) locally confined to neurons of the adjacent ganglia. Macrophages and lymphocytes are increased after ten day ligation only in the affected ganglia and are probably not involved in the induction of bradykinin receptors.
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The development of tolerance following repeated doses of morphine hinders the treatment of clinical pain. We have previously shown that morphine tolerance develops in neuropathic rats without cross-tolerance to a systemic kappa-opioid agonist; in the current work, using paw-pressure vocalization thresholds, we studied the antinociceptive effect of the peripherally-selective kappa (kappa)-opioid agonist, asimadoline, in both morphine-tolerant and opioid-naïve rats 2 weeks after sciatic nerve injury. In naïve rats, intraplantar (i.pl.) injection of asimadoline into the nerve-injured paw, at doses of 10, 15 and 20 (but not 30) microg, dose-dependently relieved the mechanical allodynia-like behaviour. ⋯ These results confirm that at low doses, asimadoline exerts its action only in the periphery. In morphine-tolerant rats (after 10 mg/kg s.c. , twice daily for 4 days) and naïve, saline-pretreated rats, asimadoline (15 microg, i.pl.) relieved the mechanical allodynia-like behaviour to the same extent, indicating no cross-tolerance between morphine and the peripherally-selective drug. Our findings show promise for the treatment of neuropathic pain with low doses of peripherally-selective kappa-opioids.