Human neuropharmacological findings with oxapadol (MD 720111), a new non-narcotic analgesic

Summary The effects of oxapadol, a new non-narcotic analgesic, were tested in man using the electrically-induced nociceptive flexion reflex in the flexor muscles of the lower limb as an index of pain. The drug caused a significant increase in the threshold of the reflex whereas no change was noted with placebo.     

Piroxicam-induced analgesia: Evidence for a central component which is not opioid mediated

Piroxicam is a nonsteroidal anti-inflammatory drug with a potent analgesic effect. In order to establish whether the analgesic action of Piroxicam has a central component, we studied the effect of the drug on the nociceptive orbicularis oculi reflexes evoked by electrical stimulation of the cornea and supraorbital nerve in healthy subjects. Piroxicam significantly suppressed the corneal reflex and R3 component of the blink reflex by 28% (p<0.05) and 50% (p<0.01), respectively. This effect was not reversed by the i.v. injection of naloxone. Beta-endorphin levels did not change. Piroxicam administration induces distinct inhibitory changes in nociceptive reflexes, which suggests that the analgesic action of the drug has a central component. The ineffectiveness of naloxone, and the lack of beta-endorphin changes, indicate that this central action is independent of the opioid system; other pain regulatory systems are probably involved.     

Piroxicam-induced analgesia: evidence for a central component which is not opioid mediated.

Piroxicam is a nonsteroidal anti-inflammatory drug with a potent analgesic effect. In order to establish whether the analgesic action of Piroxicam has a central component, we studied the effect of the drug on the nociceptive orbicularis oculi reflexes evoked by electrical stimulation of the cornea and supraorbital nerve in healthy subjects. Piroxicam significantly suppressed the corneal reflex and R3 component of the blink reflex by 28% (p < 0.05) and 50% (p < 0.01), respectively. This effect was not reversed by the i.v. injection of naloxone. Beta-endorphin levels did not change. Piroxicam administration induces distinct inhibitory changes in nociceptive reflexes, which suggests that the analgesic action of the drug has a central component. The ineffectiveness of naloxone, and the lack of beta-endorphin changes, indicate that this central action is independent of the opioid system; other pain regulatory systems are probably involved.     

Differential sensitivity of pinna reflex and esophageal temperature to clonidine in mice depleted of central noradrenaline by DSP-4

Mice injected with DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a selective noradrenergic neurotoxin, had marked depletions of central noradrenaline and an attenuated post-decapitation reflex. DSP-4-treated mice exhibited an increased sensitivity to the alpha 2-adrenoceptor agonist clonidine as measured by inhibition of the pinna reflex, but normal sensitivity as measured by hypothermia. This differential sensitivity may reflect the presence of supersensitive postsynaptic alpha 2-adrenoceptors in some, but not all, CNS regions after DSP-4 treatment.     

Conditioning of depressor responses evoked by single volleys in the aortic nerve

Summary Depressor responses evoked by single volleys in the aortic nerve are more facilitated by conditioning volleys exciting C fibers in the same aortic nerve than in the contralateral one. Conditioning volleys in A fibers do not facilitate the testing depressor responses.     

Central terminals of capsaicin-sensitive primary afferent make synaptic contacts with neuronal soma in the mouse substantia gelatinosa

Degeneration of primary afferent central terminals (C-terminals) that contact neuronal soma in the substantia gelatinosa of the spinal dorsal horn was examined by electron microscopy 2 h after s.c. injection of capsaicin into newborn and adult mice. The C-terminals were small, dark, sinuous or slender terminals with clear synaptic vesicles in the early postnatal period. They are thought to develop into scalloped CI-terminals, surrounded by dendrites and a few axonal endings, forming synaptic glomeruli. The same type of nonglomerular terminals making presynaptic contacts with neuronal soma showed degeneration in both the newborn and adult animals, and were identified as capsaicin-sensitive CI-terminals. This finding suggests that capsaicin-sensitive C-fibers have a modulatory role on their own nociceptive input besides functioning in nociceptive transmission in the substantia gelatinosa.     

Interaction between bradykinin and voltage-sensitive sodium channels in myelinated nerve fibers

The effects of externally and internally applied bradykinin on the excitability of single myelinated nerve fibers were studied. External bradykinin (10 microM) slightly prolongs the action potential of a single myelinated nerve fiber; hence, when the fibers are stimulated by long-lasting pulses, this raises the frequency of repetitive firing in sensory fibers and evokes repetitive activity in motor fibers. Under voltage-clamp conditions, sodium channel inactivation is slowed, while sodium channel activation remains unaffected. Prolonged depolarization of the membrane leads to a maintained sodium current. The voltage dependence of the steady-state sodium current inactivation (h infinity) is shifted in the depolarized direction by approximately 10 mV. Internally applied bradykinin produces a frequency-dependent block of the sodium current. The phenomena described here imply that more than one site on the sodium channel is modified by bradykinin.     

Why the “stimulus-error” did not go away

Psychologists in the early years of the discipline were much concerned with the stimulus-error. Roughly, this is the problem encountered in introspective experiments when subjects are liable to frame their perceptual reports in terms of what they know of the stimulus, instead of just drawing on their perceptual experiences as they are supposedly felt. “Introspectionist” psychologist E. B. Titchener and his student E. G. Boring both argued in the early 20th century that the stimulus-error is a serious methodological pit-fall. While many of the theoretical suppositions motivating Titchener and Boring have been unfashionable since the rise of behaviourism, the stimulus-error brings our attention to one matter of perennial importance to psychophysics and the psychology of perception. This is the fact that subjects are liable to give different kinds of perceptual reports in response to the same stimulus. I discuss attempts to control for variable reports in recent experimental work on colour and lightness constancy, and the disputes that have arisen over which kinds of reports are legitimate. Some contemporary psychologists do warn us against a stimulus-error, even though they do not use this terminology. I argue that concern over the stimulus-error is diagnostic of psychologists' deep theoretical commitments, such as their conception of sensation, or their demarcation of perception from cognition. I conclude by discussing the relevance of this debate to current philosophy of perception.     

Purification of a protein binding quinacrine and histrionicotoxin from membrane fragments rich in cholinergic receptors in Torpedo marmorata]

A protein is purified by differential centrifugation from membrane fragments rich in acetylcholine receptor prepared from Torpedo marmorata electric organ after dissolution by a mixture of non denaturing detergents. After polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate and Coomassie blue staining the purified protein yields a single band of apparent molecular weight 43,000. Spectroscopic experiments carried out in the absence of Ca++ and detergents reveal that the 43 K protein interacts with the fluorescent local anesthetic quinacrine and with the frog toxin histrionicotoxin (apparent KD : 7 X 10(-7) M) but not with carbamylcholine and the alpha toxin from N. nigricollis.     

Oculomotor reflex evoked by vibrassae stimulation in the cat]

The oculomotor effects of vibrissae stimulation have been studied in the "encéphale isolé" non-anaesthetized Cat. Intracellular recording of lateral rectus motoneurones showed an excitatory projection via the ipsilateral infraorbital nerve to these motoneurones. The afferent fibers are type A alpha, recuited with a low threshold (0.2-0.5 mA) and convey information about vibrissae displacement.     

Control of sequences of movements in crayfish escape behavior

Summary Crayfish escape from predators by a series of rapid tailflips. The production of this seemingly simple behavior involves the interaction of multiple neural control mechanisms. The rapid flexion phase of the first tailflip is a fixed action pattern that is always organized by giant command neurons. Subsequent reextension is a chain reflex mediated by sensory feedback from the initial flexion. All following tailflips are produced by a non-gialnt system which is activated in parallel with the giant system by the escape-initiating stimulus. Proper integration of the giant system and the non-giant system is mediated by a reaction time mechanism.     

Instruments of Music,Instruments of Science: Hermann von Helmholtz's Musical Practices,his Classicism,and his Beethoven Sonata

The young Hermann Helmholtz, in an 1838 letter home, declared that he always appreciated music much more when he played it for himself. Though a frequent concert-goer, and celebrated for his highly influential 1863 work on the physiological basis of music theory, Die Lehre von den Tonempfindungen, it is likely that Helmholtz's enduring engagement with music began with his initial, personal experience of playing music for himself. I develop this idea, shifting the discussion of Helmholtz's work on sound sensation back to its origins, and examine the role of his material interaction with musical instruments and music itself. In his sound sensation studies, Helmholtz understood sound as an external, physical object. But Helmholtz also conceived of sound in musical terms. Further, Helmholtz's particular musical tastes as well as his deeply personal interaction with musical instruments allowed him to reconcile his conception of sound as physical object with his conception of sound as music. Helmholtz's physiological theory of sound sensation was both the product of and constitutive of how he heard and created sound. I argue that Helmholtz himself was the embodied reconciliation of his physiological theory of sound sensation and his belief that musical aesthetics were historically and culturally contingent.     

Baroreceptors capable of inducing the biosynthesis and release of prostaglandins (PG) and of modulating adrenergic neurotransmission in the myocardium

In the isolated Rabbit heart, high pressure, on the one hand, inhibits the noradrenaline release, and on the other hand, induces both the biosynthesis and release of PGs(PGE2,PGF2 alpha) from the auricles and mainly from the right auricle i.e. where the sympathetic nerve endings are the most numerous. Therefore, high pressure, by a negative feedback process, plays a great part in moderating the adrenergic neurotransmission responsible for the hypertension. These effects result from a supplementary pressure which acts on the walls of coronary arteries and arterioles and modifies their distensibility. It thus appears that in the walls of arteries and arterioles there are baroreceptors which are sensitive to the pressure variations in order to regulate adrenergic neurotransmission, by means of a reflex path still unknown.     

Stimulation parameters determine role of GABAB receptors in long-term potentiation

Blockade of GABA_B receptors was reported to improve cognitive performance in mammals. The physiological basis of this effect is poorly understood. We investigated the effect of the GABA_B receptor antagonist CGP 35348 on long-term potentiation (LTP) in the CA1 area of the hippocampus in vitro and in vivo. In vitro the effect of CGP 35348 on LTP, induced either by two non-primed tetanic stimulations or by two primed bursts of stimuli, was investigated. In the presence of 1 mM CGP 35348 LTP was significantly facilitated following two non-primed tetanic trains, but was impaired following two primed burst stimulations. In vivo LTP was induced by applying non-primed trains of stimuli of increasing duration to the Schaffer collateral/commissural fibers. The potentiation of the population spike recorded in CA1 was significantly facilitated by CGP 35348 (100 mg/kg i.v.). In conclusion these findings demonstrate that the GABA_B antagonist CGP 35348 facilitates LTP in vitro and in vivo if induced by non-primed tetanic stimulation. In vitro, the mode of stimulation determines the effect of the GABA_B antagonist on LTP.     

Interaction between visual activation and proprioceptive activation in neurons of the superior colliculus]

Units located in the superficial and intermediate layers of the superior colliculus are activated by proprioceptive stimulation of the extraocular muscle nerves as well as by specific visual stimuli. Units of the deep layer of the colliculus, not sensitive to visual activation, are inhibited by proprioceptive stimulation. A few of the units showed interaction between the two types of stimulation, the proprioceptive response appearing only when spontaneous activity was decreased by a visual stimulus.     

Multifunctional interneurons in behavioral circuits of the medicinal leech

Summary We are using the medicinal leech to study the neuronal basis of behavioral choice. In particular, we are recording from neurons, both extracellularly and intracellularly, in preparations that can express three different behaviors: the shortening reflex, crawling and swimming. We have found that particular mechanosensory neurons can elicit any of the behaviors, and that the movements are produced by just four sets of muscles, each controlled by a small number of motor neurons. Hence, there must be three different pattern-generating neuronal circuits, each of which can be activated by the same set of sensory neurons. We are studying how the choice is made among the three behaviors by recording, while one behavior is being performed, from neurons known to be involved in the initiation of the other two. We have found that an interneuron, cell 204, which is known to initiate and maintain swimming, is also active during shortening and crawling. The activity level in this interneuron can influence whether a mechanosensory stimulus produces shortening or swimming. The neuronal mechanisms by which this choice is normally effected awaits further elucidation of the circuits that elicit and generate shortening and crawling.     

Sympathetic preganglionic pupillodilator fibres in the light reflex

Summary The modifications of the sympathetic pupillodilator activity in the light reflex have been demonstrated by recording the electrical discharge of single preganglionic fibres in the cervical sympathetic nerve.This work was supported by a grant of CNR.     

Multifunctional interneurons in behavioral circuits of the medicinal leech

We are using the medicinal leech to study the neuronal basis of behavioral choice. In particular, we are recording from neurons, both extracellularly and intracellularly, in preparations that can express three different behaviors: the shortening reflex, crawling and swimming. We have found that particular mechanosensory neurons can elicit any of the behaviors, and that the movements are produced by just four sets of muscles, each controlled by a small number of motor neurons. Hence, there must be three different pattern-generating neuronal circuits, each of which can be activated by the same set of sensory neurons. We are studying how the choice is made among the three behaviors by recording, while one behavior is being performed, from neurons known to be involved in the initiation of the other two. We have found that an interneuron, cell 204, which is known to initiate and maintain swimming, is also active during shortening and crawling. The activity level in this interneuron can influence whether a mechanosensory stimulus produces shortening or swimming. The neuronal mechanisms by which this choice is normally effected awaits further elucidation of the circuits that elicit and generate shortening and crawling.     

The cellular immune response to heat shock proteins.

T lymphocytes, which are central to almost every immune response, frequently recognize microbial hsp60. Such cells could provide an early defense mechanism against pathogenic microbes. However, T cells also recognize epitopes of hsp60 shared by microbe and host. Not only conventional alpha/beta T cells respond to hsp60; gamma/delta T cells do so, as well. In fact, certain gamma/delta T cells seem to have a particular preference for this molecule. Recognition of stressed host cells expressing hsp60 could facilitate the scavenger function of the T cell system. On the other hand, such recognition could be involved in autoimmune disease.