Articles: hyperalgesia.
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Archiv der Pharmazie · Jul 2011
Synthesis and pharmacological evaluation of a potent and selective σ1 receptor antagonist with high antiallodynic activity.
Based on the pharmacophore model of Glennon the conformationally restricted σ(1) receptor ligand 2 with a 1,3-dioxane moiety has been designed and synthesized. The three step synthesis (transacetalization with pentane-1,3,5-triol, tosylation, and nucleophilic substitution with benzylamine) provided diastereoselectively the cis-configured 1,3-dioxane 2 in good yields. ⋯ In the capsaicin assay 2 showed extraordinarily high analgesic activity with more than 70% analgesia at the very low dose of 0.25 mg/kg body weight, which indicates σ(1) antagonistic activity. Since 2 does only interact with σ(1) receptors, the in-vivo antiallodynic activity of 2 must be attributed to the σ(1) antagonistic activity.
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Chronic widespread pain, such as observed in irritable bowel (IBS) and fibromyalgia (FMS) syndrome, are markedly affected by stress. While such forms of stress-induced hyperalgesia are generally considered manifestations of "central sensitization," recent studies in patients with IBS and FMS suggest an additional, peripheral contribution. ⋯ Stress also induced an increase in conduction velocity from 1.25 m/s to 2.09 m/s, and increased variability in neuronal activity. Given that these changes, each of at least moderate magnitude, would be expected to enhance nociceptor activity, it is likely that, taken together, they contribute to the enhanced nociception observed in this model of stress-induced chronic widespread pain.
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Neuropathic pain is currently being treated by a range of therapeutic interventions that above all act to lower neuronal activity in the somatosensory system (e.g. using local anesthetics, calcium channel blockers, and opioids). The present review highlights novel and often still largely experimental treatment approaches based on insights into pathological mechanisms, which impact on the spinal nociceptive network, thereby opening the 'gate' to higher brain centers involved in the perception of pain. Cellular and molecular mechanisms such as ectopia, sensitization of nociceptors, phenotypic switching, structural plasticity, disinhibition, and neuroinflammation are discussed in relation to their involvement in pain hypersensitivity following either peripheral neuropathies or spinal cord injury. ⋯ Subsequently, identification of the therapeutic window-of-opportunities for each specific intervention in the particular peripheral and/or central neuropathy is essential for successful clinical trials. Most of the cellular and molecular pain mechanisms described in the present review suggest pharmacological interference for neuropathic pain management. However, also more invasive treatment approaches belong to current and/or future options such as neuromodulatory interventions (including spinal cord stimulation) and cell or gene therapies, respectively.
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It has been reported that intracerebroventricular injection of a μ receptor antagonist blocked 2 but not 100Hz electroacupuncture (EA)-produced analgesia in an uninjured animal model. Because persistent pain changes neural response to external stimulation, we hypothesized that the mechanisms of EA anti-hyperalgesia may be different in persistent pain than in health. Hyperalgesia, decreased paw withdrawal latency (PWL) to a noxious thermal stimulus, was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into the hind paws of rats. ⋯ In summary, EA may induce release of endogenous endomorphins that activate μ opioid receptors in GABAnergic neurons to suppress the release of GABA. This removes the tonic inhibition of GABA on serotonergic neurons in the RVM, and activation of these serotonergic neurons inhibits pain. EA may be used as complementary treatment for inflammatory pain.
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Visceral sensory afferents during disease or following injury often produce vague, diffuse body sensations, and pain referred to somatic targets. Alternatively, injury due to trauma or disease of somatic nerve targets can also lead to referred pain in visceral targets via a somatovisceral reflex. Both phenomenons are thought to be due to convergence of visceral and somatic afferents within the spinal cord. ⋯ Focal demyelination of the sciatic nerve also increased the number of injured L₄L₅ and non-injured L₆-S₂ bladder-associated sensory neurons that responded to MCP1 and SDF1 when compared with sensory neurons derived from uninjured naïve and sham-injured control animals. Taken together, these data suggest that some visceral hypersensitivity states may have a somatic origin. More importantly, nociceptive somatovisceral sensation may be mediated by upregulation of chemokine signaling in visceral sensory neurons.