Neuropharmacology
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Nefopam, a non-opioid, centrally acting benzoxazocine analgesic, proved to be as efficient in treatment of postanaesthetic thermoregulatory shivering as clonidine or meperidine. However, its exact mechanism of action is still unclear. Potent anti-shivering activity was also demonstrated for physostigmine primarily based on cholinergic but probably also different additional mechanisms of action. ⋯ In alpha(2A)-adrenoceptor knock out mice, nefopam did not affect the thermoregulatory threshold. In contrast, physostigmine decreased the thermoregulatory threshold in wildtype and all alpha(2)-adrenoceptor knock out mice independently from additional atipamezole administration. Our results indicate an important role of the alpha(2A)-adrenoceptor in the thermoregulatory response induced by nefopam but not by physostigmine in mice.
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The serotonin (5-hydroxytryptamine; 5-HT) system has a well-characterized role in depression. Recent reports describe comorbidities of mood-immune disorders, suggesting an immunological component may contribute to the pathogenesis of depression as well. Chemokines, immune proteins which mediate leukocyte trafficking, and their receptors are widely distributed in the brain, mediate neuronal patterning, and modulate various neuropathologies. ⋯ Immunohistochemical analysis further shows CXCR4 localization to DRN GABA neurons, providing an anatomical basis for CXCL12 effects on GABA release. Thus, CXCL12 indirectly modulates 5-HT neurotransmission via GABA and glutamate synaptic afferents. Future therapies targeting CXCL12 and other chemokines may treat serotonin related mood disorders, particularly depression experienced by immune-compromised individuals.
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Comparative Study
Comparison of mechanical allodynia and the affective component of inflammatory pain in rats.
Most animal models of pain cannot separate the sensory and affective components of pain. One model that has been used to assess affective pain is the place escape avoidance paradigm (PEAP). The aim of the current study is two-fold. ⋯ These results show that in inflammatory pain induced by CFA injection, PEAP is more sensitive to the effects of pain relieving compounds than mechanical allodynia. Fluoxetine showed efficacy in the mechanical allodynia test, but not PEAP, whereas duloxetine showed efficacy in mechanical allodynia and PEAP. These studies show that methods other than reflex based measures of pain such as affective pain models could be more predictive of efficacy/potency in the clinic.
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Substance P (SP) is co-localized and co-released with gamma-amino butyric acid (GABA) from approximately 50% of GABAergic medium spiny neurons (MSNs) in the striatum. MSNs innervate several cellular targets including neighboring MSNs and cholinergic interneurons via collaterals. However, the functional role of SP release onto striatal interneurons is unknown. ⋯ In addition, RP67580 alone enhanced the evoked IPSC amplitude in cholinergic interneurons, suggesting an endogenous action of SP on regulation of inhibitory synaptic transmission. SP did not alter the paired-pulse ratio, but reduced the amplitudes of GABA(A) agonist muscimol-induced outward currents and miniature IPSCs in cholinergic interneurons, suggesting SP exerts its effects primarily at the post-synaptic site. Our results indicate that the physiological effects of SP are to enhance the activity of striatal cholinergic interneurons and provide a rationale for designing potential new antiparkinsonian agents.
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Several voltage-gated sodium channels are expressed in primary sensory neurons where they control excitability and participate in the generation and propagation of action potentials. Peripheral nerve injury-induced alterations in both tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels have been proposed to contribute to neuropathic pain caused by such lesion. We herein investigated whether the blockade of TTX-sensitive channels could reduce pain-related behaviors and evoked c-Fos immunoreactivity in rats with neuropathic pain produced by chronic unilateral constriction injury to either the sciatic nerve or the infraorbital nerve. ⋯ The anti-allodynia/antihyperalgesia caused by TTX in these neuropathic rats was promoted by combined treatment with naloxone (0.5 mg/kg s.c.) but unaffected by the 5-HT(1B) receptor antagonist F11648 (0.5 mg/kg s.c.) and the alpha(2)-adrenergic receptor antagonist idazoxan (0.5 mg/kg i.v.). In contrast, the anti-allodynic and anti-hyperalgesic effects of TTX were significantly attenuated by co-administration of morphine (3 mg/kg s.c.) or the cholecystokinin(2)-receptor antagonist CI-1015 (0.1 mg/kg i.p.). These results indicate that TTX alleviates pain-related behaviors in sciatic nerve-lesioned rats through mechanisms that involve complex interactions with opioidergic systems.