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In this study, we examined whether activation of 5-HT1A receptors elicits antinociception in response to acute noxious chemical, thermal and mechanical stimuli in mice. In the writhing test, both agonists (e.g., 8-OH-DPAT, S 14671 and WY 50,324) and partial agonists (e.g., buspirone and gepirone) elicited a pronounced antinociception. However, antagonists (e.g., (-)-alprenolol and WAY 100,135) also induced antinociception and, at lower (inactive) doses, failed to modify the action of agonists. In addition, the separation between doses required for induction of antinociception as compared to those required for induction of ataxia (in the rotarod test) was variable and low for both agonists (median: 1.9) and partial agonists (median: 1.3), although it was somewhat greater for antagonists (> or = 3.3). In the hot-plate test, only certain agonists (e.g., 8-OH-DPAT) and partial agonists (e.g., gepirone) elicited antinociception and their actions were not attenuated by 5-HT1A antagonists which, themselves, were inactive in this paradigm. The 5-HT1C/2 antagonist, ritanserin, the 5-HT3 antagonist, ondansetron, the dopamine D2 receptor antagonist, raclopride, and the alpha 1-adrenoceptor antagonist, prazosin, were also ineffective in modifying the antinociception evoked by 5-HT1A agonists and partial agonists in the hot-plate test. In contrast, their actions were strongly attenuated by the alpha 2-adrenoceptor antagonist, idazoxan. In the tail-flick tests to noxious heat and noxious pressure, 5-HT1A receptor agonists, partial agonists and antagonists generally failed to induce antinociception. Moreover, modulation of stimulus intensity (from very weak to very intense) did not reveal any influence upon the latency to respond. In conclusion, in the writhing test, the data provide no evidence for a specific antinociceptive effect of the activation of 5-HT1A receptors. Further, in the hot-plate test, for those 5-HT1A agonists and partial agonists which induce antinociception, alpha 2-adrenoceptors rather than 5-HT1A receptors are implicated in their actions. Finally, in reflexive tests, irrespective of stimulus quality or intensity, 5-HT1A agonists and partial agonists do not mediate antinociception. These data suggest that the activation of 5-HT1A receptors does not, under these conditions of acute noxious stimulation, elicit antinociception.

The prevalence of anti-HCV was determined in 1,309 leprosy patients and a control group of 1,469 subjects from 6 sub-Saharan African countries and the Yemen. Sera found positive by an initial second generation ELISA were subjected to 3 additional confirmatory tests. The anti-HCV prevalence in leprosy patients (7.1%) was significantly higher than in the control group (2.6%). HCV seroprevalence increased with age in both the control and leprosy groups. No statistically significant difference could be found between anti-HCV prevalence and the several clinical forms of leprosy among patients. The results of this study indicate a high degree of exposure or chronic carriage of hepatitis C among leprosy patients. © 1994 Wiley-Liss, Inc.

In view of the involvement of central alpha 1-adrenoceptors in the expression of 5-HT1A receptor-mediated spontaneous tail-flicks (STFs) in the rat, this study examined whether the putative alpha 1-adrenoceptor antagonist (alpha 1-antagonist) properties of certain 5-HT1A receptor agonists, (+)-flesinoxan and LY 165,163, might modify their behavior in the STF paradigm. Whereas the 5-HT1A receptor agonists 8-OH-DPAT and WY 48,723 dose-dependently elicited STFs, (+)-flesinoxan was only weakly active and LY 165,163 was ineffective. Further, (+)-flesinoxan and LY 165,163 antagonized the induction of STFs by 8-OH-DPAT and WY 48,723. Nevertheless, (+)-flesinoxan and LY 165,163 mimicked 8-OH-DPAT and WY 48,723 in eliciting a pronounced rise in plasma corticosterone and a marked hypothermia: these actions were blocked by the 5-HT1A receptor antagonist, (-)-alprenolol, but they were not affected by the alpha 1-antagonist prazosin. Reflecting its antagonist actions at alpha 1-adrenoceptors, prazosin evoked a pronounced ptosis, an action mimicked by the preferential alpha 1A-antagonists WB 4101, methylurapidil and benoxathian, whereas chlorethylclonidine, which irreversibly inactivates alpha 1B- but not alpha 1A-adrenoceptors, was inactive. Although 8-OH-DPAT and WY 48,723 failed to modify palpebral aperture, (+)-flesinoxan and LY 165,163 provoked a ptosis, suggesting that they possess alpha 1A-antagonist properties. The alpha 1-agonists cirazoline and ST 587 did not elicit STFs alone and failed to modify the induction of STFs by 8-OH-DPAT and WY 48,723. By contrast, they greatly facilitated the ability of both (+)-flesinoxan and LY 165,163 to induce STFs. STFs elicited by (+)-flesinoxan and LY 165,163 in the presence of cirazoline or ST 587 were blocked not only by prazosin but also by (-)-alprenolol, BMY 7378 and S 15535, all of which are antagonists of postsynaptic 5-HT1A receptors. The facilitatory actions of cirazoline and ST 587 were selective in that they did not permit the induction of STFs by agonists at other 5-HT receptor subtypes (5-HT1B, 5-HT1C, 5-HT2 or 5-HT3). In conclusion, in the STF paradigm, the high-efficacy agonist actions of (+)-flesinoxan and LY 165,163 at 5-HT1A receptors are "masked" by their "intrinsic" alpha 1A-antagonist properties, the neutralization of which by alpha 1-agonists reveals the activation of 5-HT1A receptors.

Spontaneous tail-flicks (STFs) in the rat are mediated by postsynaptic serotonin (5-HT)1A receptors in lumbar spinal cord (Bervoets et al., 1993). In this study, we examined the role of alpha 1- as compared with alpha 2-adrenoceptors in their modulation. STFs elicited by the 5-HT1A agonist 8-OH-DPAT were potently blocked by the alpha 1-adrenoceptor antagonist prazosin, as well as by WB 4101 and 5-methylurapidil, antagonists with a preference for the alpha 1A-subtype of adrenoceptor. In contrast, several alpha 2-antagonists, for example, idazoxan and the preferential alpha 2D-antagonist BRL 44408, (biphasically) potentiated 8-OH-DPAT-induced STFs. Whereas STFs were unaffected by the alpha 1-adrenoceptor agonist cirazoline, they were blocked both by the alpha 2-agonist UK 14,304 and by the preferential alpha 2D-agonists guanfacine and guanabenz. The intrathecal administration onto lumbar spinal cord of prazosin or of the preferential alpha 1A-antagonist benoxathian (which does not cross the blood-brain barrier) blocked STFs evoked by s.c. injection of 8-OH-DPAT. Intrathecal UK 14,304 acted similarly. Conversely, STFs elicited by intrathecal 8-OH-DPAT were blocked by s.c. prazosin or UK 14,304. Cirazoline and the preferential alpha 1A-agonist methoxamine (which does not cross the blood-brain barrier) elicited STFs upon intrathecal administration onto lumbar but not cervical spinal cord. The action of cirazoline was blocked by s.c. prazosin but not by 5-HT1A antagonists such as (-)-alprenolol, indicating that the alpha 1-adrenoceptors mediating STFs lie downstream of 5-HT1A receptors. Further, cirazoline-induced STFs were not affected by alpha 2-agonists and -antagonists, suggesting that the alpha 2-adrenoceptors inhibiting STFs are localized presynaptically to these alpha 1-adrenoceptors. In rats in which lumbar spinal cord pools of noradrenaline were depleted by 6-hydroxydopamine, STFs evoked by cirazoline were potentiated, indicating supersensitivity of postsynaptic alpha 1-adrenoceptors. In contrast, 8-OH-DPAT-induced STFs were diminished. In conclusion, spinal populations of alpha 1 (alpha 1A)- and alpha 2 (alpha 2D)- adrenoceptors respectively mediate and inhibit the induction of STFs by 5-HT1A receptor agonists, the actions of which depend on a functionally intact, descending, noradrenergic projection to lumbar spinal cord.

The novel benzodioxopiperazines [4-(benzodioxan-5-yl)1-[2- (benzocyclobutane-1-yl)ethyl]piperazine] (S 14489), [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine)] (S 15535) and [4-(benzodioxan-5-yl)1-[2(indan-1-yl)ethyl]piperazine (S15931) competitively displaced the binding of [3H]-8-OH-DPAT at serotonin (5-HT)1A receptors with affinities (pKis) of 9.2, 8.8 and 8.9, respectively. These values compared favorably with those of the structurally related eltoprazine (8.0) and the proposed 5-HT1A antagonists NAN-190 (9.2), MDL 73005 EF (8.9), SDZ 216-525 (8.8), BMY 7378 (8.7), (-)-tertatolol (8.1), (-)-alprenolol (7.7), WAY 100,135 (7.5) and spiperone (6.9). The affinities of S 14489, S 15535 and S 15931 for other 5-HT receptor types (5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 and 5-HT3) were about 50 to 1000-fold lower. The spontaneous tail-flicks, flat-body posture and hypothermia mediated by an action of the 5-HT1A agonist 8-OH-DPAT at postsynaptic 5-HT1A receptors were dose-dependently and completely antagonized by S 14489, S 15535 and S15931 at doses of 0.63 to 10.0 and 2.5 to 40.0 mg/kg for s.c. and oral administration, respectively. They did not induce these responses alone, and in their presence, dose-response curves for 8-OH-DPAT were shifted in parallel to the right without loss of maximal effect. By contrast, eltoprazine, MDL 73005 EF, BMY 7378 and NAN-190 behaved as "partial" agonists and only incompletely antagonized the actions of 8-OH-DPAT in these tests. At 5-HT1A autoreceptors, S 14489, S 15535 and S 15931 acted as agonists in inhibiting striatal 5-hydroxytryptophan accumulation (0.16-2.5 mg/kg, s.c.) and in abolishing the electrical activity of the dorsal raphe nucleus (0.005-0.100 mg/kg, i.v.). Eltoprazine, BMY 7378, NAN-190 and MDL 73005 EF also behaved as agonists at these 5-HT1A autoreceptors, whereas WAY 100,135, spiperone, (-)-tertatolol, (-)-alprenolol and SDZ 216-525 inhibited neither accumulation nor firing. WAY 100,135 and spiperone antagonized the inhibition of DRN firing induced by S 14489, S 15535 and S 15931. The affinity of 15535 for dopamine D1 and D2 receptors, as well as for beta-, alpha 1- and alpha 2-adrenoceptors, was100-fold lower than its affinity for 5-HT1A receptors. Further, in vivo, at doses of 10.0 to 40.0 mg/kg, s.c., it showed minimal activity in tests of dopamine D2 (and D1) receptor-mediated activity. Similarly, in vivo, S 15535 was weakly active in a test of alpha 1-adrenoceptor-mediated activity.(ABSTRACT TRUNCATED AT 400 WORDS)

A study of B\'enard-Marangoni convection in containers of small aspect ratio (defined as the ratio of the diameter of the container to the depth of the liquid) is presented. In this situation, sidewall constraints have an important role in selecting the pattern at the onset of convection. In many situations, this pattern is axisymmetric with well-distributed azimuthal nodal lines (simple mode). When increasing an external parameter (supercritical heating), more complex dynamics can appear due to secondary instabilities. The experimental results presented here show that patterns beyond threshold can be just simple modes, a linear combination of simple modes, or more complicated structures that cannot be described just by superposition of a few modes. These experimental results are compared with some theoretical models, based on amplitude equations, and on a generalized Swift-Hohenberg equation. Whereas the former approach provides a simple and straightforward description for certain patterns near threshold, simulations of the latter give many of the patterns observed in the experiments.

Peripheral blood leucocytes from 9 paucibacillary and 12 multibacillary leprosy patients, from 18 healthy controls and from 34 healthy leprosy contacts were stimulated with three mycobacterial heat shock proteins with respective molecular weights of 70, 65 and 18 kDa and with the secreted 30-32 kDa protein, also called antigen 85. Antigen 85 was found to be the most powerful T-cell antigen (as measured by lymphoproliferation and IFN-gamma secretion), eliciting a positive response in all (100%) paucibacillary patients and in all lepromin-positive controls and contacts. The three heat shock proteins (hsp) were less active T-cell stimuli. Reactivity to the 70 kDa hsp was found in only 44% of the paucibacillary patients, in 80% of the lepromin-positive controls and in 60% of the lepromin-positive leprosy contacts. The 65 kDa hsp stimulated T cells in 89% of the paucibacillary patients and in 80% of the lepromin-positive controls and contacts. Responsiveness to the 18 kDa hsp, finally, was clearly more frequent in tuberculoid leprosy patients (78%) than in lepromin-positive controls (40%) or lepromin-positive leprosy contacts (4%). T-cell reactivity of 8 lepromin-negative controls, of 9 lepromin-negative contacts and of 12 multibacillary leprosy patients was low to all the antigens tested. Although proliferative and IFN-gamma responses were generally closely related, some subjects demonstrated a dissociation of these two immune parameters. Our data confirm previous findings on the powerful T-cell stimulatory properties of antigen 85 during M. leprae infection and suggest that this antigen is indeed a potentially protective T-cell immunogen.

We report two cases of leprosy in HIV-infected patients who, by their clinical, histological and immunological features, enhance the evidence that HIV-positive leprosy does not differ from nonHIV-positive leprosy. Moreover, extensive studies of reversal reactions in HIV-positive patients might be of great interest in determining the exact pathogenesis of this leprosy reactional state.

T cell proliferation and interferon (IFN)-gamma secretion were analyzed in 45 leprosy contacts stimulated with antigen 85 (Ag85), the major culture filtrate antigen from Mycobacterium bovis bacille Calmette-Guerin. All 14 Mitsuda reaction-positive contacts reacted to Mycobacterium leprae and Ag85. Three Mitsuda reaction-negative contacts reacted weakly to M. leprae and Ag85. The other 28 Mitsuda reaction-negative contacts did not react to M. leprae, but 9 reacted to Ag85. Thirty-four contacts were retested 16 months later. Eleven contacts initially positive by the Mitsuda test remained lepromin positive and reactive to M. leprae and Ag85. Fourteen contacts initially negative by the Mitsuda test converted, and all reacted in vitro to M. leprae and Ag85. Finally, 9 contacts remained Mitsuda test-negative, and 7 were unreactive to Ag85. In vitro reactivity to Ag85 at baseline in Mitsuda test-negative contacts was associated with subsequent conversion to lepromin reactivity in 7 of 9 subjects. These data suggest that reactive T cells against Ag85 develop very early during M. leprae infection and that Ag85 is a potentially protective T cell immunogen.

We present here a simple method for the direct evaluation of traces of p-order replacement operators (p-RO's) calculated in a finite-dimensional, antisymmetric, and spin-adapted N-electron space. The procedure is based on the reduction of the operator order together with a performance of the summations through Slater determinants. Very useful and general formulas, which can be applied to RO's of any order p\ensuremath{\le}N, are then derived.

Guanine nucleotide binding proteins (GTP-binding proteins) function as transducers of signals in different cellular processes. We have identified several GTP-binding proteins in Trypanosoma cruzi by Western blot analyses. Six polypeptide bands, p20, p25, p28, p31, p37 and p38, were specifically detected in epimastigote crude extracts, using polyclonal antibodies directed against transducin (T) or the alpha-subunit of transducin (T alpha). Four of these bands, p28, p31, p37 and p38, were found in both the soluble and the particulate epimastigote fractions. On the other hand, two of the polypeptides, p20 and p25, were observed only in the particulate fraction, and were not solubilized using 0.2% Triton X-100 and 0.2% Nonidet P-40. A rat monoclonal antibody directed against the ras oncogene, immunorecognized a band with molecular mass of 20,000 daltons, in epimastigote homogenates. In view of their identical apparent molecular weight and solubilization properties, p20, recognized by anti-T or anti-T alpha antibodies, and the 20 KDa band, recognized by anti-ras antibodies, seem to correspond to the same polypeptide. [3H] GDP and [3H] GMP-PNP binding experiments revealed the presence of guanine nucleotide binding proteins in total epimastigote crude extracts, as well as, in the soluble, detergent soluble, and particulate fractions. A primary screening of a T. cruzi cDNA library with anti-T alpha antibodies, followed by secondary and tertiary screenings with anti-ras antibodies yielded six positive clones. One of these clones (Tc-ras1) contains a 600 bp insert which we believe encodes for the ras protein from T. cruzi. On a Northern blot, this cDNA hybridizes to a unique mRNA band of 2.0 Kilobases in epimastigotes.

Central opioid analgesics such as morphine are universally employed in the alleviation of severe and, in particular, chronic pain. In view of their key importance, there is continuing interest in the mechanisms underlying their analgesic actions and in the functional response of endogenous opioid systems to chronic pain. It is with the latter of these themes that the present review is concerned. The multiplicity of endogenous opioid systems is addressed in detail in other chapters in this volume and summarized in Table 1. The relationship between multiple opioid peptides, on the one hand, and multiple opioid receptors, on the other, is still unclear. Nevertheless, it seems that dynorphin A1 – I7 (DYN) and other products encoded by the gene for pro-dynorphin (PDYN), such as DYN A1 – 8 DYN B, and α neo- endorphin, act via κ-receptors. Pro-enkephalin (PENK)-derived opioids such as met-enkephalin (ME) and ME-Arg-Gly-Leu (MERGL) possibly exert their actions via δ-receptors, though this is still not certain. β-Endorphin (β-EP) can act via μ- and δ-receptors and has, in addition, been proposed to interact with a so-called e-receptor. (As there is no relevant information concerning this site and chronic pain, it is not further discussed herein.) μ-,δ- and κ-receptors can each mediate antinociception at cerebral and spinal sites and may interact in the expression of their antinociceptive effects (BESSE et al. 1990; JIANG et al. 1990; MIASKOWSKI et al. 1990a; SUTIERS et al. 1990; see HEYMAN et al. 1988; MILLAN 1986, 1990; see also Chaps. 32 and 33).

The present study examined the location of the serotonin (5-HT)1A receptors mediating the induction of spontaneous tail-flicks (STFs) in the rat. Serotoninergic neurones were lesioned by i.c.v. administration of 5,7-dihydroxytryptamine, which depleted levels of 5-HT in the spinal cord and other CNS tissues by90% without affecting those of noradrenaline and dopamine. In lesioned rats, the ability of the 5-HT releasers, para-chloroamphetamine and methylenedioxymethamphetamine, to elicit STFs was abolished. In contrast, the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)- tetralin (8-OH-DPAT), continued to evoke STFs. In fact, its effect was significantly enhanced in lesioned as compared with sham animals. In (nonlesioned) rats with catheters chronically implanted at the lumbar spinal level, intrathecal 8-OH-DPAT dose-dependently evoked STFs. The action of 8-OH-DPAT was extremely rapid, being maximal within 1 min of injection. Whereas the 5-HT1B/C agonist, TFMPP, the 5-HT1C/2 agonist, DOI, and the 5-HT3 agonist, m-chlorophenylbiguanide, failed to elicit STFs, the action of 8-OH-DPAT was mimicked by several other 5-HT1A agonists: S 14671, 5-MeODMT and lisuride. These also showed a time-course with a rapid onset. Further, the highly hydrophilic 5-HT1A agonist, 5-carboxyamidotryptamine, which fails to pass the blood-brain barrier, likewise dose-dependently elicited STFs upon direct lumbar administration. In contrast, administered onto the cervical spinal cord, it was completely ineffective. Systemic administration of the 5-HT1A antagonists, BMY 7378 or (-)-alprenolol, but not of the 5-HT1C/2 antagonist, ritanserin, nor of the 5-HT3 antagonist, ondansetron, blocked STFs elicited by lumbar administration of 8-OH-DPAT. Conversely, lumbar (but not cervical) administration of BMY 7378 and (-)-alprenolol dose-dependently blocked the action of systemic 8-OH-DPAT. These data demonstrate that STFs in the rat are mediated by 5-HT1A receptors postsynaptic to 5-HT neurones and localized in the lumbar spinal cord. Further, they support the concept of a relationship between STFs and mechanisms of primary sensory (nociceptive) processing.

Binding of leprosy sera to peripheral nerve from different species (mouse, guinea pig and rabbit) was evaluated by ELISA. A majority of sera, whatever the clinical form of leprosy, bind to these antigens. Absorption with Mycobacterium bovis BCG demonstrated that these antibodies recognize cross-reactive epitopes between peripheral nerve and mycobacteria. In immunoblot analysis, both leprosy patient sera and a monoclonal antibody directed at the 65 kDa heat shock protein of M. leprae were shown to react with a heat-shock 67-68 kDa sciatic nerve protein. Binding of the monoclonal antibody to this sciatic nerve antigen was prevented by incubation with lepromatous patient sera, showing that some peripheral nerve epitopes recognized by patient antibodies are shared by the 65 kDa heat shock protein of M. leprae.

The interaction at 5-hydroxytryptamine (5-HT) receptors of the novel naphtylpiperazine, S 14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7- methoxynaphtyl)]piperazine), was compared to that of the 5-HT1A ligands, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), WY 50,324 [N-(29(4-(2-pyrimidinyl)-1-piperazinyl)ethyl)tricyclo(3.3.1.1(3,7) )- decane-1-carboxamide], (+)-flesinoxan, buspirone and BMY 7378 [(8-[2-[4-(2-methoxyphenyl)- 1-piperazinyl]ethyl]-8-azaspirol[-4-]-decane-7,9-dione 2HCl]. S 14671 showed a very high affinity for 5-HT1A sites (pKi, 9.3) as compared to the reference ligands (pKi values, 9.2, 8.7, 8.7, 7.9 and 8.7, respectively). S 14671 bound in an apparently competitive manner and, in distinction to the reference compounds, possessed a Hill Coefficient (1.4) significantly superior to 1. Although showing low affinity at 5-HT1B and 5-HT3 sites, S 14671 displayed significant affinity at both 5-HT1C and 5-HT2 sites; pKi, 7.8 in each case. Furthermore, S 14671 acted as an antagonist of 5-HT-stimulated phosphoinositide turnover in rat choroid plexus (5-HT1C) and cortex (5-HT2). In vivo, upon s.c. administration, S 14671 acted as a high efficacy agonist in models of 5-HT1A receptor-mediated activity: induction of flat-body posture, spontaneous tail-flicks, hypothermia and corticosterone secretion and inhibition of morphine-induced antinociception. In every test, S 14671 was the most potent compound: it was active at doses as low as 5 micrograms/kg s.c. Relative potency across all tests was S 14671 greater than 8-OH-DPAT greater than WY 50,324 greater than (+)-flesinoxan greater than buspirone with BMY 7378 too weak for comparison to be meaningful. The action of S 14671 in 5-HT1A tests was blocked by BMY 7378 and the 5-HT1A antagonist, (-)-alprenolol, but unaffected by the 5-HT1C/2 antagonist, ritanserin, and the 5-HT3 antagonist, ondansetron. Activation of postsynaptic 5-HT1A receptors was confirmed in 5,7-dihydroxytryptamine-lesioned rats, in which the potency of S 14671 to elicit spontaneous tail-flicks was potentiated. Activation of presynaptic receptors was demonstrated by inhibition of the electrical activity of the dorsal raphe nucleus with the following order of relative potency: S 14671 greater than 8-OH-DPAT greater than WY 50,324 greater than BMY 7378 greater than buspirone. Spiperone, which acts as a pure 5-HT1A antagonist at raphe 5-HT1A receptors, blocked the action of S 14671. In conclusion, S 14671 is a structurally novel ligand manifesting high efficacy and exceptional potency at both pre- and postsynaptic 5-HT1A receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

In order to learn more about early nerve lesions observed in leprosy, we performed a clinical, electrophysiological and morphological study in seven patients with untreated lepromatous leprosy, palpably enlarged radial cutaneous nerve and preserved sensation in the corresponding territory. The conduction velocity of the cutaneous radial nerve, which was decreased in all patients, did not significantly differ from that of a group of patients with lepromatous leprosy, hypertrophy of the radial cutaneous nerve and sensory loss. In contrast, the sensory action potential was significantly lower in patients with sensory loss, which demonstrates that axon loss is more important than demyelination in producing sensory loss. In all patients nerve enlargement was due to thickening of the epineurium and of the perineurium subsequent to inflammatory infiltrates and proliferation of fibroblasts and perineurial cells. In several fascicles, the inflammatory infiltrates and the infected cells infiltrated endoneurial connective tissue septa and blood vessels.Mycobacteria leprae were abundant in peri neurial cells, fibroblasts, macrophages, Schwarm cells and endothelial cells, and lymphocytic vasculitis present in all cases. The average density of myelinated fibres was 2600 SD 880 fibres/mm2 (control: 7700 fibres/mm2), with marked differences between individual fascicles, versus 420 fibres/mm2 in patients with nerve hypertrophy and sensory loss (range 0–2080 fibres/mm2). Single fibre preparations showed that segmental demyelination pre dominated in two patients, axonal degeneration in one, while inflammatory infiltrates and proliferation of connective tissue adhering to individual fibres were prominent in the others. Both infection of Schwann cells and secretory products released by mononuclear cells involved in the inflammatory process are likely to play a role in the lesions of nerve fibres observed in early stages of lepromatous leprosy.

We have measured the role of serum components on two parameters of the phagocytosis reaction: a) the chemiluminescence (CL) response associated with the oxidative respiratory burst in response to Mycobacterium bovis BCG and M. leprae, and b) the uptake of these two mycobacteria by healthy human monocytes. Pre-incubations of fresh or heat-inactivated serum or serum containing EGTA or EDTA indicate that these two mycobacteria activate the alternative complement pathway. Monoclonal antibodies against CR1 and CR3 inhibit the responses of M. bovis BCG and M. leprae, demonstrating that complement receptors mediate the phagocytosis of these two mycobacteria. Thus, complement and its receptors on the surface of the monocytes (CR1 and CR3) are important in the functional activation of phagocytosis of M. bovis BCG and M. leprae.

The purpose of the study is to propose a simple and reproducible test for assessing nerve damage in leprosy. It is applied to the sensory branch of the radial nerve of leprosy patients, prior to any treatment. Skin sensitivity is measured by means of a needle, a drop of ether and some calibrated filaments. These three tests are collated and compared with the results of electromyographic examination of the nerve. The filament calibrated to 0.2 grams gives optimum sensitivity (0.79) and excellent specificity (0.95) in relation to the electromyographic test. Its routine use in the field is simple and reproducible and should result in a greater number of patients receiving the treatment they need.

The novel antidepressant, agomelatine, behaves as an agonist at melatonin MT(1) and MT(2) receptors and as an antagonist at serotonin (5-HT)(2C) receptors. In animal models and clinical trials, agomelatine displays antidepressant properties and re-synchronizes disrupted circadian rhythms.The objectives of this study were to compare the influence of agomelatine upon sleep-wake states to the selective melatonin agonists, melatonin and ramelteon, and to the selective 5-HT(2C) receptor antagonist, S32006.Rats were administered with vehicle, agomelatine, ramelteon, melatonin, or S32006, at the onset of either dark or light periods. Polygraphic recordings were performed and changes determined over 24 h, i.e., number and duration of sleep-wake episodes, latencies to rapid eye movement (REM) and slow-wave (SWS) sleep, power band spectra of the electroencephalogram (EEG), and circadian changes.Administered at light phase onset, no changes were induced by agomelatine. In contrast, administered shortly before dark phase, agomelatine (10 and 40 mg/kg, per os) enhanced duration of REM and SWS sleep and decreased wake state for 3 h. Melatonin (10 mg/kg, per os) induced a transient enhancement in REM sleep followed by a reduction in REM and SWS sleep and an increase in waking. Ramelteon (10 mg/kg, per os) provoked a transient increase in REM sleep. Finally, S32006 (10 mg/kg, intraperitoneally), administered at dark phase onset, mimicked the increased SWS provoked by agomelatine, yet diminished REM sleep.Agomelatine possesses a distinctive EEG profile compared with melatonin, ramelteon, and S32006, possibly reflecting co-joint agonist and antagonist properties at MT(1)/MT(2) and 5-HT(2C) receptors, respectively.

Mycobacterium leprae, in contrast to BCG, failed to trigger any chemiluminescence (CL) response in mononuclear cells from either leprosy patients or healthy subjects, a deficit not reversed by either interferon-gamma or GM-CSF. Chemiluminescence responses induced without mycobacteria or with BCG were found to be lower in leprosy patients than in controls. M. leprae were also less well phagocytosed than BCG. However, there was a significant difference in phagocytosis between healthy and tuberculoid leprosy subjects. Phagocytosis was not altered by the addition of either lymphokine, and no major differences between healthy subjects and patients were observed. Preincubating mononuclear cells with anti-mycobacteria antibodies (lepromatous patients' sera) did not increase the CL response nor the phagocytosis of M. leprae or BCG.

This study pharmacologically characterizes a novel behavioral response as a potential in vivo model of serotonin (5-HT)1A receptor-mediated activity. In rats restrained in horizontal cylinders, the selective 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin HBr (8-OH-DPAT), dose-dependently (0.04-10.0 mg/kg s.c.) elicited spontaneous tail-flicks (STFs). This action was mimicked by other ligands possessing high affinity and high efficacy at 5-HT1A sites: RU 24969 [(5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole], lisuride, (+)-lysergic acid diethylamide and 5-methoxy-N,N-dimethyltryptamine hydrogen oxalate. The response could not be elicited by CGS 12066B [7-trifluormethyl-4-(4-methyl-l-piperazonyl)-pyrrolol- [1-2-a] quinoxaline dimaleate], mCPP 1-(3-chlorophenyl)-piperazine-2-HCl, TFMPPm-trifluromethylphenylpiperazine HCl, MK 212 [6-chloro-2-(l-piperzinyl)pyrazine], quipazine and DOI (+-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane HCl, which act in vivo as agonists at 5-HT1B, 5-HT1C and/or 5-HT2 receptors, or by the 5-HT3 agonist, 2-methyl-5-HT. p-chloroamphetamine, which releases endogenous 5-HT, also evoked STFs; in contrast, d-amphetamine, a preferential releaser of catecholamines, was inactive, as were agonists and antagonists at alpha-1, alpha-2, beta-1, beta-2, dopamine D1 and D2 sites. 8-OH-DPAT-elicited STFs were blocked by the 5-HT1/2 antagonist, methiothepin, but not by the 5-HT1C/5-HT2 antagonists, mianserin, ritanserin and ICI 169,369 [2-(2-dimethylaminoetheylthio)-3-phenylquinoline] nor by the 5-HT3 antagonists, GR 38032F [(1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-l-yl)methyl]-4H- carbazol-4-one HCl], ICS 205,930 [(3 alpha-tropanyl)-1H-indol-3-carboxylic acid ester] and MDL 72222 [(1 alpha H, 3 alpha, 5 alpha H)-tripan-3-yl-3,5- dichlorobenzoate]. beta-Blockers with 5-HT1A affinity i.e., (-)-alprenolol, (+/-)-isamoltane and, stereoselectivity, (-)-but not (+)-pindolol, blocked the action of 8-OH-DPAT. Spiperone and spiroxatrine, D2 antagonists with high 5-HT1A affinity, also inhibited 8-OH-DPAT-induced STFs. Selective beta-blockers and D2 antagonists with low 5-HT1A affinity were inactive. 5-HT1A partial agonists, the pyrimidinylpiperazines, buspirone, gepirone and ipsapirone, the halogenated phenylpiperazine, LY 165,163 [1-(2-(4-aminophenyl) ethyl-4-(3-trifluoromethylphenyl)-piperazine], and the benzodioxane, MDL 72832 [8-(4-(1,4-benzodioxan-2-yl-methylamino)-butyl-8-azaspiro-(4 ,5)-decane- 7,9-dione] did not elicit STFs and antagonized the effect of 8-OH-DPAT.(ABSTRACT TRUNCATED AT 400 WORDS)

This study examined the effects of structurally diverse 5-hydroxytryptamine (HT)1A partial agonists upon opioid-induced antinociception against noxious heat and pressure stimuli in rats and mice. The pyrimidinylpiperazines, buspirone, ipsapirone and gepirone, the halogenated phenylpiperazine, LY 165, 163 [1-(2-(4-aminophenyl)ethyl-4-(3-trifluoromethylphenyl)-piperazine], the heterobicylic arylpiperazine, (+/-)-flexinoxan, and the benzodiaxane, MDL 728328-[(4-(1,4-benzodioxon-2-ylmethylamino)butyl-8-azasp iro-(4,5)-decane-7,9-dione], exerted little or no effect upon basal latencies. In both mice and rats, each dose-dependently attenuated the antinociceptive action of the mu-opioid, morphine, against heat and pressure. In their presence, the morphine dose-response curve was shifted in parallel to the right with no loss of maximal effect. In mice, Schild analysis of the action of ipsapirone and gepirone yielded slopes of close to -1. In contrast to the partial agonists, the buspirone metabolite, 1-pyrimidinylpiperazine, which lacks 5-HT1A affinity, and the putative 5-HT1A antagonists, methiothepin, spiperone, BMY 7378 [(8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol [4]-decane-7,9-dione) 2HCl] and alprenolol, did not reduce the action of morphine. In rats, the antagonistic effect of buspirone, gepirone and ipsapirone could be blocked by BMY 7378. The 5-HT1A partial agonists also antagonized the antinociception-induced by the mu-opioid, sufentanil, but were virtually inactive against the selective kappa-opioid agonists, U69,593 (5 alpha,7 alpha,8 beta-(+)-N-methyl-N-[7-(l-pyrrolidinyl)-1-oxaspirol-(4,5)-dec-8-yl ] benzene-acetamide) and U50,488H (trans-(dl)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzenacetamide methane sulfonate hydrate.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to investigate the mechanisms by which gastrin cause GH release in humans we measured the GH response to pentagastrin alone (1.5 micrograms/kg/hour from 120 to 210 min) and following pretreatment with GHRH (GHRH 1-29,250 micrograms, iv at 0 min) in normal male subjects. Prior GHRH administration abolished the GH response to the second bolus of GHRH (1 micrograms/kg) administered two hours later. Pentagastrin infusion induced a rise in GH levels maximal at 60 min (9.1 + 0.6 ng/ml, mean + SE), but this rise was abolished by pretreatment with GHRH. Finally, we found that gastrin did not modify basal GH release or GH responses to GHRH by rat anterior pituitary cells in monolayer culture. Taken together, these data suggest that gastrin regulates GH secretion by acting at hypothalamic level.

This study examined the influence of s.c. administration of 5-hydroxytryptamine (HT)1A agonists upon the antinociceptive action of s.c. injected morphine in tail-flick tests to noxious heat and pressure. The selective 5-HT1A agonist, (+-)-8-hydroxy-diprolaminotetralin HBr (8-OH-DPAT), dose-dependently antagonized morphine-induced antinociception (MIA) without affecting the latency to respond when applied alone. In the presence of increasing doses of 8-OH-DPAT (0.16-0.63 mg/kg), the morphine dose-response curve was shifted progressively in parallel to the right and the maximal effect of morphine was not altered; Schild analysis yielded a slope of close to -1.0. 8-OH-DPAT both prevented and reversed the action of morphine. The action of 8-OH-DPAT was reversible (at 24 hr). In distinction, 8-OH-DPAT neither blocked morphine-induced Straub tail nor precipitated withdrawal in morphine-dependent animals; thus, it lacked opioid-antagonist properties. The antagonism of MIA by 8-OH-DPAT was mimicked by additional drugs acting as high efficacy 5-HT1A agonists: lisuride, 5-methoxy-N,N-dimethyltryptamine hydrogen oxalate, RU 24969 [methoxy-3-(1,2,3.6-tetrahydropyridin-4-yl)-1H-indole] and d-lysergic acid diethylamide. In contrast, the 5-HT1B/1C agonist, TFMPP m-trifluromethylphenylpiperazine HCl, and the 5-HT1C/2 agonist, DOI (+-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane HCI, were ineffective. The putative selective 5-HT1A antagonists, BMY 7378 [(8-[-[4-(2-,ethoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol[4]- decane-7,9-dione-2-HCL] and spiperone, did not reduce MIA. Indeed, BMY 7378 blocked the ability of 8-OH-DPAT to antagonize MIA. Under the present conditions, agonists and antagonists at adrenergic and dopaminergic receptors did not attenuate MIA. These data show that, over a certain range of doses, the systemic administration of 8-OH-DPAT and other high efficacy 5-HT1A agonists functionally antagonizes the antinociceptive action of systemically applied morphine in a competitive-like manner. It is suggested that 5-HT1A receptors play an important role in the modulation of opioidergic antinociceptive mechanisms.

Our current inability to satisfactorily manage pain, in particular chronic pain, represents a serious clinical problem and a continuing challenge to basic research and drug development. Morphine and similar opioids are ubiquitously employed for the treatment of severe and/ or long-term pain. However, certain types of pain are refractory to the application of opioids and there are significant drawbacks associated with their usage, e.g. respiratory depression, emesis, development of tolerance, and their abuse potential. It is arguable that the more judicious and intelligent administration of opioids by thoroughly trained physicians (specializing in pain management) would substantially contribute to the overcoming of such problems. Nevertheless, the conviction remains that there is a need for alternative modes of pain therapy and that an enhanced understanding of the operation of systems physiologically involved in the response to pain should facilitate the development of novel analgetic agents.

Introduccion. Las estatinas representan un grupo de farmacos con eficacia probada y escasos efectos secundarios; sin embargo, su amplia difusion aumenta la probabilidad de su aparicion. Desarrollo. Revisamos los articulos publicados sobre miotoxicidad, neurotoxicidad y otros casos de afectacion del sistema nervioso periferico, tanto en revisiones como en ensayos clinicos y casos aislados, analizando la frecuencia de aparicion, la repercusion clinica, los mecanismos fisiopatogenicos propuestos y extrayendo la actitud terapeutica que debe tomarse. Conclusiones. En general son farmacos seguros, pero el facultativo debe prestar atencion a la aparicion de posibles efectos adversos dada su potencial reversibilidad y menor gravedad si se diagnostican de forma precoz.

Over the past decade, opioids have attracted great attention. One important reason for this is the need for novel, strong analgesics free of the abuse potential and side-effects of narcotics such as morphine. Because morphine acts at mu-opioid receptors, efforts have been made to characterize analgesia mediated by non-mu sites, in particular kappa-opioid receptors. There is now good evidence that kappa-receptors do indeed mediate analgesia. However, kappa-agonists display properties that could curtail their therapeutic exploitation. Since the first selective kappa-agonists are now entering clinical trials, this is an opportune moment for Mark Millan to review the pharmacology of drugs of this type in the control of nociception and their therapeutic potential as analgesics.

Inoculation of the right hind paw with Mycobacterium butyricum led to an inflammation reflected in a reduction in the threshold to respond to noxious pressure. Chronic perfusion of naloxone at a 'high' dose of 3.0 mg/kg/hr blocked the antinociceptive action of the mu-agonist, morphine, and the kappa-agonist, U69 593. In contrast, a 'low' dose of 0.16 mg/kg/hr antagonized the action only of morphine. Two days postimplantation, the hyperalgesia to pressure was potentiated in rats receiving the high, but not the low dose of naloxone. At 6 days, this difference was no longer seen. At 7 days, pumps were removed; one day later, in rats which had been receiving the high, (but not low) dose of naloxone, thresholds on the inflamed paw no longer differed from those on the uninflamed paw. This may reflect supersensitivity to an endogenous opioid. The data suggest that kappa-receptors may contribute to control of nociception in inflammatory pain. However, this role does not appear to be essential.

One of the central issues in present experimental pain research is to establish the identity, location, and mechanism of action of various opioids (opioid peptides and alkaloids) and multiple opioid receptors in the modulation of nociceptive processes. At the cerebral level, studies employing several experimental approaches point to an essential role of beta-endorphin in analgesia, induced by electrical stimulation of the periaqueductal grey of the midbrain. Tolerance and cross-tolerance studies suggest that mu-opioid receptors mediate this effect. The significance of delta- and, in particular, chi-opioid receptors in cerebral pain modulation is less well documented. At the spinal level, nociception is relayed in the dorsal horn, where opioid peptides as well as all types of opioid receptors are abundant. mu-opioid receptor-mediated antinociceptive processes appear to be most important in this region, but delta-opioid receptors may also be involved. In addition, a role of chi-opioid receptors can be demonstrated under certain conditions. Recent experiments indicate that opioids may also modulate nociception in the periphery, in particular in inflamed tissue. The identification of opioid receptors and their endogenous ligands, the opioid peptides, marked the beginning of a new era in pain research. The differentiation of several types of opioid receptors and the subsequent characterization of a series of opioid peptides illustrate the striking complexity of opioid systems. The implications of this multiplicity for neurobiology in general and for the understanding of pain mechanisms in particular are presently not fully understood. In this presentation some aspects of opioidergic pain control at various levels of the neuraxis will be discussed.