The past decade has seen important advances in the clinical use of serotonergic agents. The authors summarize the current status of selective agents for 5-HT receptor subtypes and their utility in the treatment of human neuropsychiatric disorders. The putative novel anxiolytic effects of 5-HT1A partial agonists such as buspirone, the unique and potent antiemetic effects of 5-HT3 antagonists in cancer chemotherapy, and the antidepressant effects of selective 5-HT uptake blockers such as fluoxetine are excellent examples of the clinical relevance of selective 5-HT receptor agents. The increasing ability to modulate serotonergic neurotransmission via distinct serotonin (5-HT) receptor subtypes should greatly facilitate the analysis of the role of 5-HT in both normal and abnormal human brain function.
Article abstract-Nerve growth factor (NGF) plays a biologic role in the development and maintenance of sympathetic and small sensory neurons. Because it facilitates nerve fiber regeneration, lowers heat-pain threshold (hyperalgesia), and prevents or improves nerve dysfunction in experimental neuropathy, it is being considered as a putative treatment for certain human polyneuropathies. In 16 healthy subjects, we tested whether intradermal injection of minute doses of recombinant human NGF (1 or 3 micro g) compared with saline induces hyperalgesia or alters cutaneous sensation (at the site of injection) as measured by symptom scores, clinical examination, or quantitative sensory testing with Computer Assisted Sensory Examination (CASE IV). Most subjects had, as their only symptom, localized tenderness of the NGF-injected site and only when the site was bumped or compressed. Slight discomfort developed in volar wrist structures (with flexion of fingers) or tenderness of deep structures to palpation over the bicipital groove or supraclavicular region. The Neuropathy Symptoms and Change questionnaire indicated that pressure allodynia was significantly localized to the NGF-injected side from 3 hours to 21 days after injections. Light stroking of the skin did not induce tactile allodynia. Compression of injected sites induced pressure allodynia that occurred more frequently and significantly on the NGF-injected side after 3 hours and was maintained for several weeks. No abnormality of vibratory or cooling detection threshold developed from NGF injection. By contrast, heat-pain threshold (HP 0.5, p = 0.003) and an intermediate level of heat-pain (HP 5.0, p < 0.001) were significantly lowered 1, 3, and 7 days (and in some cases at 3 hours and 14 and 21 days) after NGF injection. The time course of pressure allodynia and heat-pain hyperalgesia is too rapid to be explained by uptake of NGF by nociception terminals, retrograde transport, and upregulation of pain modulators. Local tissue mechanisms appear to be implicated. It remains to be tested whether recombinant human NGF prevents, stabilizes, or ameliorates small fiber human neuropathies. NEUROLOGY 1997;48: 501-505
The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Twenty-four patients with classic migraine attacks were treated with either nifedipine or placebo for up to 12 weeks. No significant differences were observed between the nifedipine (2.1 ± 0.2) and placebo (2.3 ± 0.2) treatment groups in the monthly frequency of headaches. However, the incidence of side effects was significantly greater (p < 0.001) in the nifedipine (54% of patients) than in the placebo (8% of patients) treatment groups.
5-Hydroxytryptamine (5-HT) is known to act in peripheral tissues to produce pain and inflammation, yet the mechanisms underlying 5-HT-induced inflammation have not been well studied. The present study uses a rat knee joint model of inflammation (synovial plasma extravasation) and molecular biological techniques to determine the site of action of 5-HT and the specific 5-HT receptor subtype mediating synovial 5-HT-induced plasma extravasation. 5-HT (1 microM) stimulates synovial plasma extravasation 7-fold above base-line levels. Surgical lumbar sympathectomy, but not C-fiber depletion by neonatal capsaicin, dramatically reduces 5-HT-induced synovial plasma extravasation (P < .001), indicating that sympathetic efferents mediate this effect. Polymerase chain reaction amplification of 5-HT receptor cDNA demonstrates that 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A and 5-HT3, but not the 5-HT2C, receptor subtypes are present in lumbar sympathetic ganglia. With selective ligands for these receptor subtypes, we demonstrate that 5-HT-induced synovial plasma extravasation is mediated via the 5-HT2A receptor. These findings suggest a role for 5-HT2A antagonists in various synovial inflammatory pain states.
Abstract Familial hemiplegic migraine (FHM) is an autosomal dominant disorder characterized by transient hemiplegia during the aura phase of a migraine attack. Nystagmus has been reported in individuals affected with this disorder, but the origin of the ocular motility findings is unknown. A three‐generation family with FHM is described and clinical histories are outlined. Ocular motility evaluations were performed on 7 family members, 5 with a history of hemiplegic migraine and 2 without history of migraine. All affected family members had abnormal eye movements consistent with vestibulocerebellar dysfunction. Magnetic resonance imaging scans in affected family members revealed cerebellar vermian atrophy. DNA linkage analysis revealed a common marker in all the affected family members on chromosome 19. We suggest that the hemiplegic migraine attacks and the cerebellar degeneration are linked genetically and that the eye movements are not the ischemic sequelae of recurrent migraine. Strikingly similar ocular motility findings and cerebellar degeneration are reported in both FHM and a genetically related disorder, hereditary paroxysmal cerebellar ataxia (HPCA). The significance of these similarities is discussed along with a proposed pathophysiology for FHM.
