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 micrograms) 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.

Abstracr: Significant advances in the molecular pharmacological analysis of 5-hydroxytryptamine (5-HT) receptor subtypes occurred in the 1980's. To a significant degree, this progress resulted from 2 independent approaches: molecular biology and molecular pharmacology. This review focuses on the pharmacological data derived from radioligand binding studies. At the present time, 5-HT receptor subtypes are often categorized into at least 3 major "families" as well as a few "orphan" receptors that cannot yet be placed into the major categories. Each "family" consists of multiple receptor subtypes which share similarities in their molecular biological, pharmacological, biochemical and physiological properties. In order to provide a comparative pharmacological analysis of the 7 most extensively characterized 5-HT receptor subtypes, potency information is presented on the 30 pharmacological agents that have been, to date, studied most extensively in the published literature. Abbreviations:mCPP, m-chlorophenylpiperazine; 5-CT, 5-carboxyamidotryptamine; DHE, dihydroergotamine; DOB, 4-bromo-2,5-dimethoxyamphetamine; DOI, 4-iodo-2,5-dimethoxyamphetamine; GRANISETRON, (endo-N-(methyl-9-abicyclo-[3. 3.l]-non-3-yl)-l-methyl-indazol-3-carboxamide;carboxylic acid ester; I-CYP, iodo-cyanopindolol; d-LSD, d-lysergic acid diethylamide; MDL 72222, I-alphaH-3alpha-5-alphaH-tropan-3-yl-3,5-dichlorobenzoate; MDL 72832, 8-[4-[( 1,4-benzodioxan-2-ylmethyl)amino]butyl]-8-azaspiro[4.5]decane-7,9-dione; 5-MDMT, 5-methoxydimethyltrytamine; 5-MeO-DPAC, 5-methoxy-3-(di-n-propylamino)chroman; 8-MeO-N-PAT, 8-methoxy-2[N-propyl-N-propylamino]tetralin; 5-MT, 5-methoxytryptamine; 8-OH-DPAT, 8-hydroxy-2-(di-N-propylamino)-tetralin; ONDANSETRON, (1,2,3,9-tetrahydro-9-methyl-3[(2-methyl-1H-imidazol-l-yl)methy1]-4-one; PAPP, 1[2-(4-aminophenyl)ethyl]-4-(3tnfluoromethylphenyl)-pi~razine); QUIPAZINE, 2 4 I-piperaziny1)quinoline; RU 24969, 5-methoxy-3-[ 1,2,3,6-tetrahydro-4-pyridinyl]-I H-indole; SCH 23390, 7-chloro-8-hydroxy-1-phenyl-2,3,4,5-te~~ydro-lH-3-benzazepine; TFMPP, trifluoromethylpiperazine; WB 41 01, 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1.4-benzo-dioxane; ZACOPRIDE, 4-amino-N-( l-azabicyclo[2. 2.2]oct-3-yl)-5-chloro-2-methoxy~~ideThis review will focus on the current status of 5-HT receptor subtypes in terms of their molecular biological and pharmacological properties. The pharmacological data are derived from the analysis of radioligand binding studies, a technique which has proved to be remarkably accurate in identifying and characterizing 5-HT receptor subtypes during the past decade. The data summarized in this review are derived from a radioligand binding study database, established in this laboratory, which currently includes 3400 separate drug affinity values that were collated from a total of 121 published papers. In order to provide a comparative pharmacological analysis of the major 5-HT receptor subtypes, potency information was collated on the 30 pharmacological agents that have been, to date, studied most extensively in the p...

The radioligand binding characteristics of 125I-R-(-)4-iodo-2,5-dimethoxyphenylisopropylamine [125I-R-(-)DOI] and 3H-ketanserin were compared in rat and bovine cortical membranes. In rat cortex, 125I-R-(-)DOI labels a relatively low density of binding sites (Bmax = 2.5 +/- 0.2 pmol/gm tissue) with high affinity (KD = 0.63 +/- 0.09 nM). In bovine cortex, specific binding of 125I-R-(-)DOI represents less than 20% of total binding at radioligand concentrations above 0.6 nM, and, therefore, the data cannot be analyzed adequately by Scatchard transformation. By contrast, 3H-ketanserin displays saturable, specific high-affinity binding in both rat cortex (KD = 1.0 +/- 0.1 nM; Bmax = 11 +/- 0.4 pmol/gm tissue) and bovine cortex (KD = 1.2 +/- 0.2 nM; Bmax = 5.3 +/- 0.4 pmol/gm tissue). Ki values for 30 drugs were determined for 125I-R-(-)DOI-labeled sites in rat cortex and 3H-ketanserin-labeled sites in bovine cortex. 5-Hydroxytryptamine (5-HT) displays 250-fold higher selectivity for the 125I-R-(-)DOI-labeled sites (Ki = 3.0 +/- 0.7 nM) than for the 3H-ketanserin-labeled sites (Ki = 750 +/- 50 nM). Structural congeners of R-(-)DOI display 80- to 160-fold higher affinity for the 125I-R-(-)DOI binding site than for the 3H-ketanserin-labeled binding site. d-LSD and putative 5-HT2 antagonists are approximately equipotent at both sites. Significant correlations were found between drug affinities for 125I-R-(-)DOI-labeled sites in rat cortex and putative 5-HT2A sites labeled previously by 77Br-R-(-)DOB (r = 0.93, p less than 0.01), putative 5-HT2B sites labeled by 3H-ketanserin in bovine cortex (r = 0.63, p less than 0.01), and 5-HT1C binding sites that have been characterized by other investigators (r = 0.78, p less than 0.01). No significant correlations were found between drug affinities for 125I-R-(-)DOI-labeled sites in rat cortex and 5-HT1A, 5-HT1B, 5-HT1D, or 5-HT3 sites, as determined by previous investigators. We conclude that 125I-R-(-)DOI labels a novel 5-HT binding site subtype (tentatively designated the 5-HT2A binding site) that is present in rat cortex but is either absent or minimally present in bovine cortex. By contrast, 3H-ketanserin labels both the putative 5-HT2A site in rat cortex as well as a separate, distinct recognition site that is present in both rat and bovine cortex, tentatively designated the 5-HT2B site.

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.

We conducted a multicenter, double-blind, parallel-group study to compare the efficacy and safety of dihydroergotamine (DHE) nasal spray and placebo over 4 hours in the treatment of migraine. Of the 112 patients enrolled, 100 were included in the "intent-to-treat" efficacy analysis. The patients self-administered either 2.0 mg DHE (0.5 mg per nostril, repeated after 15 minutes) or placebo at the onset of two separate headaches and rated hourly the drugs' effects on pain severity, pain relief, nausea, and vomiting. The physicians assessed the overall effectiveness of the drugs in relieving headache pain, nausea, and vomiting. Both the patients' and physicians' ratings indicated that DHE was significantly superior to placebo in improving headache and nausea; according to the patients' ratings, these between-group differences were already significant at the first (hour 1) evaluation. There were no significant differential treatment effects with respect to relief of vomiting. Most adverse events were mild or moderate, confined to the nasopharyngeal area, and probably related to the route of administration. We conclude that DHE nasal spray is a safe and effective treatment for the pain and nausea of migraine attacks.

This review describes a novel genetic approach to the assessment of receptor function that is based on association studies of polymorphisms within human genes. The realization that variations within human genes may significantly affect gene function has led to increased use of this approach in recent years. Analysis of polymorphisms within the human 5-HT2A receptor is used as a specific example of the application of association genetics to elucidate gene function. The interaction of many neuroleptics and antidepressants with 5-HT2A receptors points up the potential importance of this receptor for understanding and treating neuropsychiatric disorders such as schizophrenia and depression.

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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 less than 0.001) in the nifedipine (54% of patients) than in the placebo (8% of patients) treatment groups.