THE evaluation of pain in the human fetus and neonate is difficult because pain is generally defined as a subjective phenomenon.1 Early studies of neurologic development concluded that neonatal responses to painful stimuli were decorticate in nature and that perception or localization of pain was not present.2 Furthermore, because neonates may not have memories of painful experiences, they were not thought capable of interpreting pain in a manner similar to that of adults.3 4 5 On a theoretical basis, it was also argued that a high threshold of painful stimuli may be adaptive in protecting infants from pain during birth.6 These traditional . . .

Pain and its effects in the human neonate and fetus

During the last decade, the GH axis has become the compelling focus of remarkably active and broad-ranging basic and clinical research. Molecular and genetic models, the discovery of human GHRH and its receptor, the cloning of the GHRP receptor, and the clinical availability of recombinant GH and IGF-I have allowed surprisingly rapid advances in our knowledge of the neuroregulation of the GH-IGF-I axis in many pathophysiological contexts. The complexity of the GHRH/somatostatin-GH-IGF-I axis thus commends itself to more formalized modeling (154, 155), since the multivalent feedback-control activities are difficult to assimilate fully on an intuitive scale. Understanding the dynamic neuroendocrine mechanisms that direct the pulsatile secretion of this fundamental growth-promoting and metabolic hormone remains a critical goal, the realization of which is challenged by the exponentially accumulating matrix of experimental and clinical data in this arena. To the above end, we review here the pathophysiology of the GHRH somatostatin-GH-IGF-I feedback axis consisting of corresponding key neurotransmitters, neuromodulators, and metabolic effectors, and their cloned receptors and signaling pathways. We propose that this system is best viewed as a multivalent feedback network that is exquisitely sensitive to an array of neuroregulators and environmental stressors and genetic restraints. Feedback and feedforward mechanisms acting within the intact somatotropic axis mediate homeostatic control throughout the human lifetime and are disrupted in disease. Novel effectors of the GH axis, such as GHRPs, also offer promise as investigative probes and possible therapeutic agents. Further understanding of the mechanisms of GH neuroregulation will likely allow development of progressively more specific molecular and clinical tools for the diagnosis and treatment of various conditions in which GH secretion is regulated abnormally. Thus, we predict that unexpected and enriching insights in the domain of the neuroendocrine pathophysiology of the GH axis are likely be achieved in the succeeding decades of basic and clinical research.

Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human

N Engl J Med 2003;349:1943-53. Copyright © 2003 Massachusetts Medical Society. pium is a bitter, brown, granular powder derived from the seedpod of the poppy ( Papaver somniferum ). People have used opium for the relief of pain and suffering for thousands of years. Before the 19th century, opium was cultivated and used chiefly in the Middle East, whereas in Europe and the United States it was a luxury available mainly to the elite. During the 19th century, several historical events conspired to make opium and other opioids more readily available. The production of opium increased rapidly, and after the morphine alkaloid was identified in 1806 pharmacologic production of opioid drugs began. Use of morphine-containing tinctures such as laudanum became commonplace, especially in the treatment of the “travails” and “boredom” of Victorian women. Morphine-containing cures for colic, diarrhea, dysmenorrhea, and other painful conditions were widely available and could be bought from doctors and pharmacists. With the rise of the “street use” of opium and heroin, legal controls were introduced. In the United States, the first attempts to control the abuse of narcotics came at the end of the 19th century, when a few states instituted limited controls. By the 1940s, opioids were so tightly restricted that they could be used legally only when they were prescribed by physicians according to strict regulatory controls. The legal use of opioids was thus placed entirely in the hands of physicians, who were, and still are, liable to lose their medical licenses and risk criminal prosecution if they prescribe these drugs inappropriately. The immediate effect of such strict regulatory control was that physicians became reluctant to prescribe opioids, and as a result pain was woefully undertreated. 1 Through the efforts of advocates of pain control, toward the end of the 20th century opioid therapy was reestablished as an invaluable and accepted treatment for acute pain, pain due to cancer, and pain caused by a terminal disease. The most difficult issue now facing physicians who treat patients with chronic pain probably is whether and how to prescribe opioid therapy for chronic pain that is not associated with terminal disease, including pain experienced by the increasing number of patients with cancer in remission who need long-term opioid therapy. Many of the issues involved in the treatment of patients with pain due to cancer in remission are the same as those in the treatment of patients with chronic pain that is unrelated to malignant conditions. Our review addresses specific questions about dose and toxicity in the light of recent studies that suggest a need to modify current practices in the use of opioid therapy for chronic pain.

Opioid therapy for chronic pain

Capsaicin-sensitive sensory neurons convey to the central nervous system signals (chemical and physical) arising from viscera and the skin which activate a variety of visceromotor and neuroendocrine reflexes integrated at various levels (intramurally in peripheral organs, at level of prevertebral ganglia, spinal and supraspinal level). Much evidence is now available that peripheral terminals of certain sensory neurons, widely distributed in skin and viscera have the ability to release, upon adequate stimulation, their transmitter content. In addition to the well-known "axon reflex" arrangement, the capsaicin-sensitive sensory neurons have the ability to release the stored transmitter also from the same terminal which is excited by the environmental stimulus. The efferent function of these sensory neurons is realized through the direct and indirect (i.e. mediated by activation of other cells) effects of released mediators. The action of released transmitters on postjunctional elements covers a wide range of effects which may have a physiological or pathological relevance. Development of drugs capable of controlling the sensory-efferent functions of the capsaicin-sensitive sensory neurons represent a new and very promising area of research for pharmacological treatment of various human diseases.

The sensory-efferent function of capsaicin-sensitive sensory neurons

Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β- and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β- and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

/pdf/amyloid-beta-structure-biology-and-structure-based-3y96h59gd4.pdf

Amyloid beta: structure, biology and structure-based therapeutic development

Anisotropic beam theory and applications

1. Although it is well known that morphine induces significant immunosuppression, the potential immunosuppressive activity of morphine derived drugs commonly used in the treatment of pain (codeine, hydromorphone, oxycodone) has never been evaluated. 2. We evaluated in the mouse the effect of the natural opiates (morphine and codeine) and synthetic derivatives (hydromorphone, oxycodone, nalorphine, naloxone and naltrexone) on antinociceptive thresholds and immune parameters (splenocyte proliferation, Natural Killer (NK) cell activity and interleukin-2 (IL-2) production). 3. Morphine displayed a potent immunosuppressive effect that was not dose-related to the antinociceptive effect, codeine possessed a weak antinociceptive effect and limited immunosuppressive activity; nalorphine, a mu-antagonist and kappa-agonist, exerted a potent immunosuppressive effect, but had very weak antinociceptive activity. The pure kappa-antagonist nor-BNI antagonized the antinociceptive, but not the immunosuppressive effect of nalorphine. 4. Hydromorphone and oxycodone, potent antinociceptive drugs, were devoid of immunosuppressive effects. 5. The pure antagonists naloxone and naltrexone potentiated immune responses. 6. Our data indicate that the C6 carbonyl substitution, together with the presence of a C7-8 single bond potentiates the antinociceptive effect, but abolishes immunosuppression (hydromorphone and oxycodone). 7. The single substitution of an allyl on the piperidinic ring resulted in a molecule that antagonized the antinociceptive effect but maintained the immunosuppressive effect. 8. Molecules that carry modifications of C6, the C7-8 bond and C14, together with an allyl or caboxymethyl group on the piperidinic ring antagonized both the antinociceptive and the immunosuppressive effect of opiates and were themselves immunostimulants.

http://europepmc.org/articles/PMC1564723?pdf=render

Antinociceptive and immunosuppressive effects of opiate drugs: a structure‐related activity study

A C 0 beam discretization based on the finite volume concept is described. In the linear case this approach leads to a collocated evaluation of the stiffness matrix of the beam; it proves to be intrinsically free from shear locking. In the nonlinear formulation only a collocated evaluation of the elastic forces is required, which dramatically simplifies the computation of the elastic contribution to the equilibrium equations. The formulation is here developed for the general geometrically nonlinear case and implemented in multibody formulation. The proposed approach proved to be consistent; its major drawback lies In the loss of symmetry of both the linear and the linearized beam matrices. For this reason the method is particularly suitable for dynamic problems like a nonlinear implicit multibody numerical approximation, in which the symmetry of the matrices is not so important, as it is already lost, whereas the ease in the generation of the contributions to the equations can lead to faster and cheaper analyses. Some applications are outlined, and the most relevant results are discussed.

Multibody Implementation of Finite Volume C-0 Beams

The analgesic effect of acute or chronic nortriptyline, amitriptyline and their effects on morphine induced analgesia were evaluated in the rat. Clomipramine and amitriptyline, but not Nortriptyline, induce analgesia, while all potentiate the effect of morphine when administered acutely. The analgesic effect of clomipramine is blunted by both the serotonin antagonist metergoline and the opiate receptor blocker naloxone, thus indicating an involvement of both the serotoninergic and endogenous opioid system. The involvement of the serotoninergic system is confirmed by the similar results obtained with the serotonin precursor 5-hydroxytryptophan administered alone or together with morphine. A relation between the serotoninergic and the endogenous opioid systems is also shown by the increase in hypothalamic beta-endorphin concentrations elicited by all the drugs used after acute or chronic treatment, with the only exception of nortriptyline, that has been shown to exert its effects mainly through the noradrenergic system. In conclusion, the analgesic effect of clomipramine and amitriptyline and their potentiation of morphine induced analgesia seems to be related to an activation of the endogenous opioid system mediated by serotonin.

Paolo Mantegazza

Papers

Anisotropic beam theory and applications

Antinociceptive and immunosuppressive effects of opiate drugs: a structure‐related activity study

Multibody Implementation of Finite Volume C-0 Beams

A role for serotonin and beta-endorphin in the analgesia induced by some tricyclic antidepressant drugs

Dynamic response of mechanical systems by a weak hamiltonian formulation