Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.

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Central sensitization: implications for the diagnosis and treatment of pain.

Opioid peptides were assayed by inhibition of 3H-naloxone and 3H-leu-enkephalin binding in brain homogenates and by depression of contractions of the guinea pig ileum and mouse vas deferens. We conclude that the opioid peptidergic system has agonists of different characteristics which interact with more than one type of receptor.

Endogenous opioid peptides: multiple agonists and receptors

Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.

/pdf/prolactin-structure-function-and-regulation-of-secretion-3w4x6fqbg3.pdf

Prolactin: Structure, Function, and Regulation of Secretion

The molecular and cellular actions of three classes of abused drugs--opiates, psychostimulants, and ethanol--are reviewed in the context of behavioral studies of drug dependence. The immediate effects of drugs are compared to those observed after long-term exposure. A neurobiological basis for drug dependence is proposed from the linkage between the cellular and behavioral effects of these drugs.

https://science.sciencemag.org/content/sci/242/4879/715.full.pdf

Cellular and molecular mechanisms of drug dependence.

Publisher Summary Turns are a fundamental class of polypeptide structure and are defined as sites where the peptide chain reverses its overall direction. In the past 20 years, the peptide field has witnessed major development, stimulated by the discovery of a host of bioactive peptides. Turn structures have been proposed and implicated in the bioactivity of several of these naturally occurring peptides. In addition, many structural details of turns have been derived from conformational studies of model peptides. During this same period, more than 100 complete protein structures have been elucidated in single-crystal X-ray studies. These examples document the rich diversity of structural patterns in the chain folds of native proteins. Turns are intrinsically polar structures with backbone groups that pack together closely and side chains that project outward. Such an array of atoms may constitute a site for molecular recognition, and indeed, the literature abounds with suggestions that turns serve as loci for receptor binding, antibody recognition, and post-translational modification. In peptides, turns are the conformations of choice for simultaneously optimizing both backbone–chain compactness (intramolecular nonbonded contacts) and side-chain clustering (to facilitate intermolecular recognition). Presence of turns in bioactive conformations may in fact also reflect the lack of alternative conformational possibilities. The aim of this chapter is to examine structural and functional roles of turns in peptides and proteins.

Turns in peptides and proteins.

Enkephalin, a natural ligand for opiate receptors is composed of the pentapepides H-Tyr-Gly-Gly-Phe-Met-OH and H-Tyr-Gly-Gly-Phe-Leu-OH. The evidence is based on the determination of the amino acid sequence of natural enkephalin by the dansyl-Edman procedure and by mass spectrometry followed by synthesis and comparison of the natural and synthetic peptides.

Identification of two related pentapeptides from the brain with potent opiate agonist activity

tion of the ipsilateral canine tooth pulp and not the contralateral one. Most were also excited by tactile stimulation of the surrounding trigeminal field. Latencies to tooth pulp stimulation ranged from 5.1 to 22.8 msec. All were located at or just below the border of the magnocellular layer of trigeminal nucleus caudalis, Another group of neurons was excited by bilateral canine stimulation. Late&es ranged from 7 to 28 msec. All were also excited by ipsilateral cornea1 mechanical stimulation and firm pressure applied to the face bilaterally. All were located deep to nucleus caudalis in a reticular area continuous with nucleus gigantocellularis of the reticular formation. It is concluded that the first class of unit is functionally similar to spinal cord dorsal horn lamina V neurons, while the second class may be the trigeminal contribution to medial spinoreticular pathways.

Pharmacology identification of two related pentapeptides from the brain with potent opiate agonist activity

The synthesis of α (?)-galactose-l-phosphoric acid has provided a means of examining the constitution of the galactosephosphate accumulating in the liver during galactose assimilation1. Both natural and synthetic esters are non-reducing, very readily hydrolysed by acid, and resistant to alkaline hydrolysis. After removal of the reducing esters by alkaline hydrolysis, the mixture of phosphoric esters isolated from the liver during galactose assimilation contained, apart from water of hydration, 29·6 per cent anhydrous barium galactose-l-phosphate, 3·1 per cent anhydrous glucose-l-phosphate, 2 per cent barium salt of an unidentified acid-labile ester, and 60 per cent barium salt of an acid-resistant ester. This mixture of barium salts had [α]5461 + 34·4° and the barium salt of the acid-resistant ester [α]5461 – 3·4°. Cori, Colowick and Cori2 found for anhydrous barium glucose-l-phosphate [α]D + 75° which corresponds to [α]5461 + 89°. By calculation from these values, natural barium galactose-l-phosphate would have [α]5461 + 114° while the corresponding value of the synthetic ester is + 110°. Determined in a similar manner, the constant of hydrolysis of the natural ester in 0·25 N HCl at 25° would be 0·87 × 10-3 while that of the synthetic ester is 0·89 × 10-3. These findings, together with the earlier evidence, make it highly probable that the galactosephosphate present in the liver during galactose assimilation is identical with synthetic α(?)-galactose-l-phosphoric acid. An attempt is being made to crystallize the natural ester as the dipotassium salt.

H. W. Kosterlitz

Papers

Identification of two related pentapeptides from the brain with potent opiate agonist activity

Pharmacology identification of two related pentapeptides from the brain with potent opiate agonist activity

Galactose-I-Phosphoric Acid in Galactose Metabolism