Articles: hyperalgesia.
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Our aim was to quantify spatial differences in pressure and thermal pain sensitivity maps between patients with unilateral lateral epicondylalgia (LE) and age- and sex-matched controls. Pressure (PPT), cold (CPT), and heat (HPT) pain thresholds were assessed over 12 points forming a 3 × 4 matrix (4 points in the superior part, 4 points in the middle, and 4 points in the lower part around the lateral epicondyle) bilaterally in 16 subjects with strictly unilateral LE and 16 age- and sex-matched controls in a blinded design. Topographical pain sensitivity maps to pressure and thermal stimulation over the elbow in patients with LE and healthy controls were calculated. A multilevel 3-way ANCOVA test was applied to detect differences in topographical maps between groups. Subjects with LE showed bilateral lower PPT, higher CPT (pain at higher temperature) and lower HPT (pain at lower temperature) at all the measurement points as compared to controls (all, P < .01). PPT were lower at points over the extensor carpi radialis brevis (ECRB) muscle as compared to points over the extensor digitorum communis muscle (P < .01) and over the extensor carpi ulnaris muscle (P < .001). CPT and HPT were not significantly different between points (P > .05). Topographical pressure and thermal pain sensitivity maps revealed bilateral hyperalgesia in patients with strictly unilateral LE. LE patients exhibited heterogeneously distributed pressure pain hyperalgesia while cold or heat maps were homogenous. The most sensitive localizations for PPT assessment corresponded to the muscle belly of the ECRB. Our results confirm the role of ECRB muscle in LE and argue for evidence of peripheral and central sensitization mechanisms in patients with strictly unilateral symptoms. ⋯ Topographical pressure and thermal sensitivity maps revealed bilateral hyperalgesia in patients with strictly unilateral lateral epicondylalgia (LE). LE patients exhibited heterogeneously distributed pressure pain hyperalgesia while cold or heat pain maps were homogenous. The most sensitive localizations for PPT assessment corresponded to the muscle belly of the ECRB.
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Bioorg. Med. Chem. Lett. · Oct 2011
Synthesis and biological evaluation of 4-piperidinecarboxylate and 4-piperidinecyanide derivatives for T-type calcium channel blockers.
To obtain selective and potent inhibitor for T-type calcium channel by ligand based drug design, 4-piperidinecarboxylate and 4-piperidinecyanide derivatives were prepared and evaluated for in vitro and in vivo activity against α(1G) calcium channel. Among them, several compounds showed good T-type calcium channel inhibitory activity and minimal off-target activity over hERG channel (% inhibition at 10 μM=61.85-71.99, hERG channel IC(50)=1.57 ± 0.14-4.98 ± 0.36 μM). Selected compound 31a was evaluated on SNL model of neuropathic pain and showed inhibitory effect on mechanical allodynia.
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J. Korean Med. Sci. · Oct 2011
Pharmacology of intracisternal or intrathecal glycine, muscimol, and baclofen in strychnine-induced thermal hyperalgesia of mice.
Glycine and γ-aminobutyric acid (GABA) are localized and released by the same interneurons in the spinal cord. Although the effects of glycine and GABA on analgesia are well known, little is known about the effect of GABA in strychnine-induced hyperalgesia. To investigate the effect of GABA and the role of the glycine receptor in thermal hyperalgesia, we designed an experiment involving the injection of muscimol (a GABA(A) receptor agonist), baclofen (a GABA(B) receptor agonist) or glycine with strychnine (strychnine sensitive glycine receptor antagonist). ⋯ Intracisternal or intrathecal administration of strychnine produced thermal hyperalgesia in mice. Glycine antagonize the effects of strychnine, whereas, muscimol or baclofen does not. Our results indicate that glycine has anti-thermal hyperalgesic properties in vivo; and GABA receptor agonists may lack the binding abilities of glycine receptor antagonists with their sites in the central nervous system.
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Although stress induces analgesia, there is evidence that stressful events may exacerbate pain syndromes. Here, we studied the effects of 1 to 3 prestressful events (days 0, 2, and 7), such as non-nociceptive environmental stress, on inflammatory hyperalgesia induced by a carrageenan injection (day 14) in 1 rat hind paw. Changes in nociceptive threshold were evaluated by the paw pressure vocalization test. The higher the number of stress sessions presented to the rats, the greater was the inflammatory hyperalgesia. Blockade of opioid receptors by naltrexone before each stress inhibited stress-induced analgesia and suppressed the exaggerated inflammatory hyperalgesia. Stressed versus nonstressed animals could be discriminated by their response to a fentanyl ultra-low dose (fULD), that produced hyperalgesia or analgesia, respectively. This pharmacological test permitted the prediction of the pain vulnerability level of prestressed rats because fULD analgesic or hyperalgesic indices were positively correlated with inflammatory hyperalgesic indices (r(2) = .84). In prestressed rats, fULD-induced hyperalgesia and the exaggerated inflammatory hyperalgesia were prevented NMDA receptor antagonists. This study provides some preclinical evidence that pain intensity is not only the result of nociceptive input level but is also dependent on the individual history, especially prior life stress events associated with endogenous opioid release. ⋯ Based on these preclinical data, it would be of clinical interest to evaluate whether prior stressful events may also affect further pain sensation in humans. Moreover, this preclinical model could be a good tool for evaluating new therapeutic strategies for relieving pain hypersensitivity.
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Nucleoside reverse transcriptase inhibitors (NRTIs) are key components of HIV/AIDS treatment to reduce viral load. However, these drugs can induce chronic neuropathic pain, leading to increased morbidity in HIV patients. This study examines the role of brain-derived neurotrophic factor (BDNF) in the spinal dorsal horn (SDH) in development of mechanical allodynia in male C57BL/6J mice treated with the NRTI stavudine (d4T). ⋯ After d4T, BDNF heterozygous mice were less allodynic than wild-type littermates, which was negated by intrathecal BDNF administration. Finally, pretreatment with intrathecal trkB-Fc chimera prior to d4T or administration of the tyrosine kinase inhibitor K252a 3 days after d4T blocked BDNF-mediated signaling, significantly attenuated the development of mechanical allodynia (trkB-Fc), and decreased neuronal activity (trkB-Fc and K252a). Taken together, these findings provide evidence that BDNF in the SDH contributes to the development of NRTI-induced painful peripheral neuropathy and may represent a new therapeutic opportunity.