Pain
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In this study, differences of unmyelinated nerve fiber density in sural nerve biopsy material from patients suffering from neuropathies of unknown origin with (n=14) or without pain (n=13) were analyzed. Immunocytochemistry was applied to differentiate afferent sensory and efferent sympathetic nerve fibers. All patients were evaluated for deficits of small fiber function with thermotesting, quantitative sudomotor-axon reflex-testing and testing of painfulness of mechanical stimuli before performing the biopsy. ⋯ There were also no histopathological differences concerning the density of afferent C-fibers. However, absolute and relative density of efferent sympathetic nerve fibers was significantly higher in patients with painful neuropathy (P<0.001), although none of the patients demonstrated clinical sympathetic abnormalities. We conclude that an imbalance between afferent and sympathetic nerve fiber density in the periphery may contribute to neuropathic pain even in those patients without obvious clinical autonomic disturbances.
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A unilateral chronic constriction injury (CCI) of the sciatic nerve produced bilateral effects in both pain related behaviors and in the pattern of forebrain activation. All CCI animals exhibited spontaneous pain-related behaviors as well as bilateral hyperalgesia and allodynia after CCI. Further, we identified changes in baseline (unstimulated) forebrain activation patterns 2 weeks following CCI by measuring regional cerebral blood flow (rCBF). ⋯ For example, the hindlimb region of somatosensory cortex was significantly activated (22%) as well as multiple thalamc nuclei, including the ventral medial (8%), ventral posterior lateral (10%) and the posterior (9%) nuclear groups. In addition, several forebrain regions considered to be part of the limbic system showed pain-induced changes in rCBF, including the anterior dorsal nucleus of the thalamus (23%), cingulate cortex (18%), retrosplenial cortex (30%), habenular complex (53%), interpeduncular nucleus (45%) and the paraventricular nucleus of the hypothalamus (30%). Our results suggest that bilateral somatosensory and limbic forebrain structures participate in the neural mechanisms of prolonged persistent pain produced by a unilateral injury.
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After mechanical injury of a peripheral nerve some axotomized afferent neurons develop spontaneous activity, which is thought to trigger abnormal pain behavior in rats and neuropathic pain in humans. Here, we analysed the ectopic activity in axotomized afferent fibers recorded from the L5 dorsal root in different time periods after L5 spinal nerve lesion and the effects of sympathectomy on it. The following results were obtained: (1) Up to 6 hours after spinal nerve transection there was almost no spontaneous activity in axotomized afferents, except short-lasting injury discharges at the time of transection; (2) Three to 8 days following spinal nerve lesion, the rate of spontaneous activity was 7.3+/-7.7 imp/s (mean+/-SD, median 5.0 imp/s, n=204); 41.6% of the spontaneously active afferent neurons exhibited a bursting pattern with interspike intervals of 32.4+/-18.3 ms; (3) Twenty to 53 days after nerve lesion the rate of spontaneous activity had decreased significantly to 3.4+/-4.3 imp/s (median 2.6 imp/s, n=120). ⋯ However, the percentage of bursting neurons and the intraburst frequency decreased significantly; (5) Spontaneous activity occurred in afferent A-fibers but not in afferent C-fibers. These results suggest that ectopic activity in axotomized afferent neurons develops within the first days after L5 spinal nerve lesion, decreases with time and is only marginally dependent on the sympathetic innervation. There was a positive correlation between this ectopic activity and the allodynia-like behavior in spinal nerve-lesioned rats.
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Oxycodone and morphine are structurally related, strong opioid analgesics, commonly used to treat moderate to severe pain in humans. Although it is well-established that morphine is a mu-opioid agonist, this is not the case for oxycodone. Instead, our recent studies have shown that oxycodone appears to be a kappa-opioid agonist (Ross and Smith, 1997). ⋯ Behaviourally, rats co-administered sub-antinociceptive doses of oxycodone and morphine were similar to control rats dosed with saline, whereas rats that received equi-potent doses of either opioid alone, were markedly sedated. These results suggest that co-administration of sub-analgesic doses of oxycodone and morphine to patients may provide excellent pain relief with a reduction in opioid-related CNS side-effects. Controlled clinical trials in appropriate patient populations are required to evaluate this possibility.(1)
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Ziconotide (SNX-111), a selective blocker of neuronal N-type voltage-sensitive calcium channels, is antinociceptive when it is administered intrathecally. It is currently under clinical investigation for the treatment of malignant and non-malignant pain syndromes. The present study was undertaken to compare and contrast antinociceptive properties of ziconotide, morphine and clonidine in a rat model of post-operative pain. ⋯ Intravenous bolus injection of 3 mg/kg (1.1 micromol/kg) ziconotide, administered either before or after incisional surgery, had no effect on thermal pain thresholds measured in either the injured or normal hindpaw. In contrast, intraperitoneal injections of 2 mg/kg (2.6 micromol/kg) morphine and 2.5 mg/kg (9.4 micromol/kg) clonidine blocked heat hyperalgesia in the injured hindpaw; morphine, but not clonidine, also elevated thermal (heat) nociceptive response thresholds in the normal hindpaw. The results of this study show that intrathecal ziconotide is antinociceptive in a rat incisional model of post-operative pain and is more potent, longer acting, and more specific in its actions than intrathecal morphine.