Peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral neural mechanisms, such as nociceptor sensitization and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central neural function may also play a significant role. In this review, we examine the clinical and experimental evidence which points to a contribution of central neural plasticity to the development of pathological pain. We also assess the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system (CNS) in response to noxious peripheral stimulation. Finally, we examine theories which have been proposed to explain how injury or noxious stimulation lead to alterations in CNS function which influence subsequent pain experience.

/pdf/contribution-of-central-neuroplasticity-to-pathological-pain-m3ucvtce0k.pdf

Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence

Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed.

Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding

Placebo

The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

https://science.sciencemag.org/content/sci/281/5383/1640.full.pdf

Distinct Mechanism for Antidepressant Activity by Blockade of Central Substance P Receptors

Peptides, as neurotransmitters, neuromodulators, and hormones, influence a multitude of physiological processes by signal transduction mediated through receptors. In addition, during the last 20 years their role in the appearance or maintenance of various diseases could be unequivocally proven. Agents that can imitate or block the biological functions of bioactive peptides (agonists or antagonists, respectively) can be considered as aids for the investigation of peptidergic systems and also as therapeutic agents. The suitability of bioactive peptides as therapeutic agents was examined after preliminary pharmacological experiments. It was thereby shown that based on their pharmacological properties, for example degradation by peptidases or poor bioavailability, they could be employed as drugs in only a few cases. To solve this problem peptidomimetics, compounds that act as substitutes for peptides in their interaction with receptors, have been synthesized. In comparison with native peptides they show higher metabolic stability, better bioavailability, and longer duration of action. Peptidomimetics with antagonistic properties were also developed within the range of these investigations. As a result, new types of treatment and therapy for a series of diseases are possible. Although peptidomimetics have been developed largely by empirical methods (e.g. modification of native peptides, optimization of lead structures), methods for rational design based on investigations into the structure of peptidepeptide receptor complexes and studies of conformation energies, among others, are gradually being established.

Peptidomimetics for Receptor Ligands—Discovery, Development, and Medical Perspectives

Chance. M. R. A. (1947). Jbid.. 89. 289-296. , --,--Cohen,’M. & Lal, H. (1964)Nature, Lond., 201, 1037. Consolo, S., Garattini, S. & Valzelli. L. (1965). J . Pharm. Pharnzacol., 17, 53-54. Fink, G. B. & Larson, R. E. (1962). . J. Pharmacol., 137, 361-364. Greenblatt, E. N. & Osterberg, A. C. (1961). Ibid., 131, 115-119. Gunn, J. A. & Gurd, M. R. (1940). J. Physiol., Lond., 97, 343-347. Hardinge, M. G. & Peterson, D. 1. (1963). J. Pharmacol., 141, 260-265. Hardinge, M. G. & Peterson, D. I. (1964). Ibid., 145, 47-51. Hohn, R. & Lasagna, L. (1960). Psychopharmacol., 1, 210-220. Weiss, S., Laties, V. G. & Blanton, F. L. (1961). Wolf, H. H. & George, D. I. (1964). J. pharm. Sci., 53, 748-752. Ibid., 132, 366-371.

The spirally cut tracheal strip preparation

Results of animal studies indicate that the hypotensive effect of prazosin is due to vasodilatation which is dependent on two discernible components of drug action: (1) direct relaxation of vascular smooth muscle and (2) interference with peripheral sympathetic function at a site distal to the alpha-adrenergic receptor.

Analysis of the hypotensive action of prazosin.

Analysis of the cardiovascular effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (Catapres).

α2- and α2-vasular adrenoceptors in the dog

In pithed dogs pressor responses to phenylephrine were completely inhibited 1 h after phenoxybenzamine 20 mg/kg i.v., but those to norepinephrine were only partially inhibited. The pressor effects of norepinephrine in phenoxybenzamine-treated animals were inhibited by yohimbine, 2.0 mg/kg i.v., but not by prazosin, 0.5 mg/kg i.v. In animals treated with phenoxybenzamine, 20 mg/kg i.v., plus propranolol, 5.0 mg/ kg i.v., the partially restored pressor response to epinephrine, and the responses to norepinephrine, were completely inhibited by yohimbine, 2.0 mg/kg i.v., partially inhibited by corynanthine, 5.0 mg/kg i.v., but not affected by prazosin, 0.5 mg/kg i.v. In additional animals treated with phenoxybenzamine plus propranolol, yohimbine, 10, 50, 200 and 500 μg/kg i.v., caused dose-related inhibition of both the partially restored pressor response to epinephrine, and the pressor responses to norepinephrine. It is concluded that: 1) phenoxybenzamine completely blocks α1, but not α2 vascular receptors; 2) the pressor effect of norepinephrine in phenoxybenzamine-treated animals, and the partially restored pressor effect of epinephrine in phenoxybenzamine-propranolol-treated animals, are both mediated by α2 vascular receptors which are resistant to blockade by phenoxybenzamine.

Complete blockade by phenoxybenzamine of alpha 1- but not of alpha 2-vascular receptors in dogs and the effects of propranolol.

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