The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

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.

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Prolactin: Structure, Function, and Regulation of Secretion

Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia

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The induction of pain: an integrative review

Tolerance to opiates reduces their effectiveness in the treatment of severe pain. Although the mechanisms are unclear, overactivity of pro-nociceptive systems has been proposed to contribute to this phenomenon. We have reported that the development of morphine tolerance significantly increased calcitonin-gene-related-peptide-like immunoreactivity (CGRP-IR) in primary sensory afferents of the spinal dorsal horn, suggesting that changes in pain-related neuropeptides in the dorsal root ganglion (DRG) neurons may be involved (Menard et al., 1996, J. Neurosci., 16, 2342-2351). Recently, we have shown that repeated morphine treatments induced increases in CGRP- and substance P (SP)-IR in cultured DRG, mimicking the in vivo effects (Ma et al., 2000, Neuroscience, 99, 529-539). In this study, we investigated the intracellular signal transduction pathways possibly involved in morphine-induced increases in CGRP- and SP-IR in DRG neurons. Repeated morphine exposure (10-20 microm) for 6 days increased the number of neurons expressing phosphorylated (p) mitogen-activated protein (MAP) kinases, including the extracellular signal-regulated kinase (pERK), c-jun N-terminal kinase (pJNK) and P38 (pP38 MAPK). The number of neurons expressing phosphorylated cAMP responsive element binding protein (pCREB) was also markedly increased in morphine-exposed cultured DRG neurons. pERK-, pP38-, pJNK- and pCREB-IR were colocalized with CGRP-IR in cultured DRG neurons. Naloxone effectively blocked these actions of morphine, whereas a selective MEK1 inhibitor, PD98059, inhibited the morphine-induced increase in the phosphorylation of ERK and CREB, and the expression of CGRP and SP. Moreover, in morphine-tolerant rats, the number of pCREB-, CGRP- and SP-IR neurons in the lumbar DRG was also significantly increased. These in vitro and in vivo data suggest that the phosphorylation of MAP kinases and CREB plays a role in the morphine-induced increase in spinal CGRP and SP levels in primary sensory afferents, contributing to the development of tolerance to opioid-induced analgesia.

Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: an in vitro and in vivo study

Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence. This study investigated the site of action of the paradoxical effects of naltrexone and the generality of this effect. The potential of ultra-low doses of naltrexone to influence morphine-induced analgesia was investigated in tests of nociception. Administration of intrathecal (0.05 and 0.1 ng) or systemic (10 ng/kg i.p.) naltrexone augmented the antinociception produced by an acute submaximal dose of intrathecal (5 g) or systemic (7.5 mg/kg i.p.) morphine in the tail-flick test. Chronic intrathecal (0.005 and 0.05 ng) or systemic (10 ng/kg) naltrexone combined with morphine (15 g i.t.; 15 mg/kg i.p.) over a 7-day period inhibited the decline in morphine antinociception and prevented the loss of morphine potency. In animals rendered tolerant to intrathecal (15 g) or systemic (15 mg/kg) morphine, administration of naltrexone (0.05 ng i.t.; 10 and 50 ng/kg i.p.) significantly restored the antinociceptive effect and potency of morphine. Thus, in ultra-low doses, naltrexone paradoxically enhances morphine analgesia and inhibits or reverses tolerance through a spinal action. The potential of naltrexone to influence morphine-induced reward was also investigated using a place preference paradigm. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference. These effects of naltrexone on morphine-induced reward may have implications for chronic treatment with agonist-antagonist combinations.

https://www.queensu.ca/psychology/sites/webpublish.queensu.ca.psycwww/files/files/Faculty/Richard%20Beninger/Beninger_prp_27.pdf

Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats.

Anticholinergics have often been found to impair choice accuracy in the radial maze. Some researchers have suggested that this indicates involvement of cholinergically innervated structures in cognitive mapping while others argue that these structures mediate working memory. However, most results are open to either interpretation since the baiting method did not allow a distinction between reference and working memory errors. To further test these hypotheses this study examined the effects of systemic scopolamine on radial maze performance, using a 4-out-of-8 baiting procedure. Food-deprived Wistar rats were pretrained until working memory choice accuracy stabilized to a criterion of 87% or better. Scopolamine (0.1, 0.4 and 0.8 mg/kg, IP, 30 min before a session) significantly increased the number of working memory errors (re-entries into baited arms) whereas reference memory errors (entries into never baited arms) did not change significantly. Observed deficits appeared not to be attributable to a drug-induced disruption of motivational systems. Results confirm the behavioural similarities between the memorial effects of hippocampectomy and anticholinergics, and implicate cholinergically innervated structures in working memory.

Differential effects of scopolamine on working and reference memory of rats in the radial maze

Antinociceptive effects of intrathecally administered F8Famide and FMRFamide in the rat.

Previous studies have suggested that the release of dopamine (DA) in the rat brain may be sensitive to modulation by opioid agents, including the endogenous opioid peptides (enkephalins and endorphins). The present study examined the effects of morphine and the enkephalin analogue D-Ala2-Met5-enkephalinamide (DALA) on the release of radiolabeled DA from superfused slices of rat brain regions. The release of preloaded [3H]DA was evoked from slices of the caudate–putamen (CP) by application of potassium (K+), nicotine (NIC), or L-glutamic acid (L-GLU). The release of [3H]DA from slices of the nucleus accumbens (NA), olfactory tubercle (OT), and substantia nigra (SN) was evoked by L-GLU. Both K+ and NIC evoked a concentration-related release of [3H]DA from CP slices. K+-induced release was only partially dependent on calcium (Ca2+), while NIC-evoked release was completely Ca2+ independent. Neither morphine nor DALA influenced the release of [3H]DA evoked by K+ or NIC. L-GLU produced a concentration-dependent...

Khem Jhamandas

Papers

Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: an in vitro and in vivo study

Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats.

Differential effects of scopolamine on working and reference memory of rats in the radial maze

Antinociceptive effects of intrathecally administered F8Famide and FMRFamide in the rat.

Regional release of [3H]dopamine from rat brain in vitro: effects of opioids on release induced by potassium, nicotine, and L-glutamic acid