Antinociceptive properties of thyrotropin releasing hormone in mice: comparison with morphine

Boschi, G; Desiles, Marguerite; Reny, Veronique; Rips, Richard; Wrigglesworth, Susan

doi:10.1111/j.1476-5381.1983.tb10499.x

Cited by 57 publications

(26 citation statements)

References 9 publications

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“…of the spinal cord, thalamus, central gray and rostral ventral medulla, specifically implicating a role for TRHR2 in mediating TRH's putative antinociceptive properties (11,13).…”

Section: Rtrhr2: a Novel Trh Receptor Not Expressed In The Pituitarymentioning

confidence: 99%

“…When injected centrally, TRH induces a short lasting supraspinal antinociception. The analgesia induced by intracerebroventricular TRH injection is powerful since it is twice as great, on a molar basis, as that of morphine (11). This TRH-induced antinociception is detected in models of chemically and mechanically, but not thermally induced pain.…”

mentioning

confidence: 95%

“…This TRH-induced antinociception is detected in models of chemically and mechanically, but not thermally induced pain. On the other hand, intrathecal TRH injections do not affect basal antinociceptive thresholds (11). However, it is known that TRH enhances spinal reflexes (both in vivo and in vitro) and modulates pain transmission (4,12,13).…”

mentioning

confidence: 99%

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Cloning and Characterization of a cDNA Encoding a Novel Subtype of Rat Thyrotropin-releasing Hormone Receptor

Cao

O’Donnell

et al. 1998

Journal of Biological Chemistry

130

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The thyrotropin-releasing hormone (TRH) 1 is a tripeptide (pyroglutamic acid-histidine-proline-amide) synthesized from a precursor polypeptide whose sequence contains 5 copies of the TRH sequence (5-7).Originally isolated from the hypothalamus, TRH is present in the central nervous system (thalamus, cerebral cortex, and spinal cord,) as well as in the periphery (pancreas, gastrointestinal tracts, and placenta). In the hypothalamus, TRH is synthesized by peptidergic neurons of supraoptic and paraventricular nuclei. It is then axonally transported to be stored in the median eminence. When secreted in the bloodstream, it reaches the pituitary where it stimulates the production of thyroid stimulating hormone which in turn stimulates the production of thyroxin (T 4 ) in the thyroid gland (8).In addition to this pivotal role in controlling the synthesis and secretion of thyroid stimulating hormone and other hormones from the anterior pituitary, TRH has been implicated as a neurotransmitter (9). TRH abundantly exists in the central nervous system and exogenous administration of TRH elicits a variety of behavioral changes (see Ref. 10 for a review).The distribution of TRH containing cells, fibers, or receptors suggests a potential role of TRH in the perception of noxious stimuli. TRH is present in the periaqueductal gray, the nuclei raphe magnus and pallidus, and the dorsal horn of the spinal cord. TRH-binding sites have been described in the brain, the pituitary, in both the dorsal and ventral horns of the spinal cord as well as in peripheral tissues. When injected centrally, TRH induces a short lasting supraspinal antinociception. The analgesia induced by intracerebroventricular TRH injection is powerful since it is twice as great, on a molar basis, as that of morphine (11). This TRH-induced antinociception is detected in models of chemically and mechanically, but not thermally induced pain. On the other hand, intrathecal TRH injections do not affect basal antinociceptive thresholds (11). However, it is known that TRH enhances spinal reflexes (both in vivo and in vitro) and modulates pain transmission (4,12,13). Although the mode of action of TRH at the level of the spinal cord is unclear, there is evidence suggesting that the TRH-induced facilitation of spinal transmission involves the activation of the N-methyl-D-asparatate receptor (14).TRH actions are mediated by the stimulation of specific cell surface receptors. Studies of pituitary TRH receptors have suggested that the TRHR1 receptor triggers the phospholipase C-protein kinase C transduction pathway (3,15). A cDNA sequence encoding a G-protein-coupled TRHR was originally isolated from mouse pituitary using an expression cloning strategy (15). Subsequently, several groups have described the cloning of rat TRH receptor cDNAs expressed in a pituitary tumor cell line (GH 3 ) or in the pituitary gland (1, 3). In addition, two isoforms of the rat TRHR have been shown to be generated from a single gene by alternative splicing (2). These isoforms are 387 and 412 amin...

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“…of the spinal cord, thalamus, central gray and rostral ventral medulla, specifically implicating a role for TRHR2 in mediating TRH's putative antinociceptive properties (11,13).…”

Section: Rtrhr2: a Novel Trh Receptor Not Expressed In The Pituitarymentioning

confidence: 99%

mentioning

confidence: 95%

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Cloning and Characterization of a cDNA Encoding a Novel Subtype of Rat Thyrotropin-releasing Hormone Receptor

Cao

O’Donnell

et al. 1998

Journal of Biological Chemistry

130

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“…It has been reported that the analgesic potency of TRH against certain chemical stimuli is comparable to that of morphine (Boschi et al 1983). …”

Section: Diencephalonmentioning

confidence: 99%

Thyrotropin-releasing hormone receptors -- similarities and differences

Sun¹,

Lu²,

Mc³

2003

Journal of Molecular Endocrinology

158

129

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“…The central signaling system of the naturally-occurring neuropeptide TRH represents a therapeutic target with multifaceted, neurotherapeutic, homeostatic, and antinociceptive effects independent of TRH's endocrine actions (Boschi et al, 1983;Gary et al, 2003). Potential clinical application of activation of this central system in treating a wide range of CNS disorders has long been recognized (Gary et al, 2003;Griffiths, 1987;Kelly, 1995) and was recently reviewed (Daimon et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

Kelly¹,

Boyle²,

Cole³

et al. 2015

Neuropharmacology

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Hardiman, O., First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models, Neuropharmacology (2014), doi: 10.1016/j.neuropharm.2014.09.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTABSTRACT JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective therapeutic candidate offering a multifaceted approach to treating neurodegeneration and other CNS conditions. The purpose of these studies was to determine the ability of JAK4D to bind to TRH receptors in human brain and to evaluate its neuropharmacological effects in neurodegenerative animal models. Additionally, JAK4D brain permeation was examined in mouse, and initial toxicology was assessed in vivo and in vitro. We report that JAK4D bound selectively with nanomolar affinity to native TRH receptors in human hippocampal tissue and showed for the first time that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus revealing a new TRH receptor subtype which represents a promising neurotherapeutic target in human brain. Systemic administration of JAK4D elicited statistically significant and clinically-relevant neuroprotective effects in three established neurodegenerative animal models: JAK4D reduced cognitive deficits when administered post-insult in a kainate (KA)-induced rat model of neurodegeneration; it protected against free radical release and neuronal damage evoked by intrastriatal microdialysis of KA in rat; and it reduced motor decline, weight loss, and lumbar spinal cord neuronal loss in G93A-SOD1 transgenic Amyotrophic Lateral Sclerosis mice. Ability to cross the blood-brain-barrier and a clean initial toxicology profile were also shown. In light of these findings, JAK4D is an important tool for investigating the hitherto-unidentified central TRH receptor subtype reported herein and an attractive therapeutic candidate for neurodegenerative disorders.

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Antinociceptive properties of thyrotropin releasing hormone in mice: comparison with morphine

Cited by 57 publications

References 9 publications

Cloning and Characterization of a cDNA Encoding a Novel Subtype of Rat Thyrotropin-releasing Hormone Receptor

Cloning and Characterization of a cDNA Encoding a Novel Subtype of Rat Thyrotropin-releasing Hormone Receptor

Thyrotropin-releasing hormone receptors -- similarities and differences

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

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