Improgan-like Analgesics: A Family of Compounds Derived From Histamine Anatgonists

Hough, L.; Nalwalk, J.B.; Menge, W.M.P.B.; Leurs, R.; Timmerman, H.

doi:10.1007/s00044-004-0012-z

Cited by 6 publications

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“…As demonstrated previously in awake animals using a variety of nociceptive tests (Li et al, 1997; Hough, 2004; Nalwalk et al, 2004), icv administration of improgan produced powerful antinociception as measured by an increase in the latency of the heat-evoked TF response (Fig. 1).…”

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“…Extensive testing with several rodent pain models has shown improgan to have the preclinical profile of an effective analgesic (Li et al, 1997; Hough, 2004; Nalwalk et al, 2004). Improgan antinociception is not mediated by known opioid or histamine receptors (Hough et al, 2000b; Mobarakeh et al, 2003), and screening at over 100 sites has not revealed the improgan molecular target (Hough, 2004). Recent studies suggest that improgan may act through an endocannabinoid mechanism (Nalwalk et al, 2006; Gehani et al, 2007), but the drug does not have measurable affinity for known cannabinoid receptors (Hough et al, 2006).…”

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Neural basis for improgan antinociception

et al. 2010

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Improgan, the prototype compound of a novel class of non-opioid analgesic drugs derived from histamine antagonists, attenuates thermal and mechanical nociception in rodents following intracerebroventricular administration. Improgan does not bind to known opioid, histamine or cannabinoid receptors, and its molecular target has not been identified. It is known however that improgan acts directly in the periaqueductal gray and the rostral ventromedial medulla to produce its antinociceptive effects, and that inactivation of the rostral ventromedial medulla prevents the antinociceptive effect of improgan given intracerebroventricularly. Here we used in vivo singlecell recording in lightly anesthetized rats to show that improgan engages pain-modulating neurons in the medulla to produce antinociception. Following improgan administration, OFF-cells, which inhibit nociception, became continuously active and no longer paused during noxious stimulation. The increase in OFF-cell firing does not represent a non-specific neuroexcitant effect of this drug, since ON-cell discharge, associated with net nociceptive facilitation, was depressed. NEUTRALcell firing was unaffected by improgan. The net response of RVM neurons to improgan is thus comparable to that evoked by μ-opioids and cannabinoids, well known RVM-active analgesic drugs. This common basis for improgan, opioid, and cannabinoid antinociception in the RVM supports the idea that improgan functions as a specific analgesic agent. Keywordspain-modulation; brainstem; rostral ventromedial medulla; ON-cells; OFF-cells Improgan (Li et al., 1996), a derivative of the histamine receptor antagonist cimetidine, produces highly effective antinociception following intracerebroventricular (icv) administration. Extensive testing with several rodent pain models has shown improgan to have the preclinical profile of an effective analgesic (Li et al., 1997;Nalwalk et al., 2004). Improgan antinociception is not mediated by known opioid or histamine receptors (Hough et al., 2000b;Mobarakeh et al., 2003), and screening at over 100 sites has not revealed the improgan molecular target . Recent studies suggest that improgan may act through an endocannabinoid mechanism (Nalwalk et al. Publisher's Disclaimer: 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 citable 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. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 September 1. al., 2007), but the drug does not have measurable affinity for known cannabinoid receptors . Several new improgan congeners with enhanced potency and/or brainpenetrating properties have been described Hough et al., 20...

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Neural basis for improgan antinociception

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“…Earlier work from one of our laboratories focused on the analgesic properties of the histamine H 2 receptor antagonist cimetidine and its congener improgan (Hough, 2004). 3 H-Cimetidine ( 3 HCIM) exhibits high-affinity, specific binding to unknown protein(s) in brain and liver which are distinct from the H 2 receptor.…”

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Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia-Relevant Isoforms

et al. 2015

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Cytochrome P450 monooxygenases (P450s), which are well-known drug-metabolizing enzymes, are thought to play a signal transduction role in m opioid analgesia and may serve as high-affinity HCIM binding sites may also be related to opioid or nonopioid analgesia. However, of the more than 100 murine P450 enzymes, the specific isoform(s) responsible for either function have not been identified. Presently, three lines of constitutive P450 gene cluster knockout (KO) mice with full-length deletions of 14 Cyp2c, 9 Cyp2d, and 7 Cyp3a genes were studied for deficiencies in proteins. Cyp2d KO and Cyp3a KO mice showed normal antinociceptive responses to a moderate systemic dose of morphine (20 mg/kg, s.c.), thereby excluding 16 P450 isoforms as mediators of opioid analgesia. In contrast, Cyp2c KO mice showed a 41% reduction in analgesic responses following systemically (s.c.) administered morphine. However, the significance of brain Cyp2c gene products in opioid analgesia is uncertain because little or no analgesic deficits were noted in Cyp2c KO mice following intracerebroventricular or intrathecalmorphine administration, respectively. These results show that the gene products of Cyp2d and Cyp3a do not contribute to m opioid analgesia in the central nervous system. A possible role for Cyp2c gene products in opioid analgesia requires further consideration.

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“…Extensive testing with tail-pinch, tail flick, hot plate, and neuropathic pain assays (Hough, 2004 and in preparation) shows a broad antinociceptive efficacy; a lack of activity by improgan on locomotor and rotorod tests suggest a true analgesic (vs. motor impairment) action (Li et al, 1997). Several congeners of improgan with considerably higher potency and/or brain-penetrating properties have been recently discovered (Hough et al, 2005; Hough et al, 2006; Hough et al, 2007).…”

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confidence: 99%

Non-opioid antinociception produced by brain stem injections of improgan: Significance of local, but not cross-regional, cannabinoid mechanisms

2009

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Improgan, a cimetidine derivative which lacks activity at known histamine, opioid or cannabinoid receptors, acts by an unknown mechanism in the periaqueductal gray (PAG) and raphe magnus (RM) to stimulate descending, analgesic circuits. These circuits may utilize cannabinoid mechanisms. To characterize further the nature of these circuits, the effects of intracerebral (i.c.) microinjections of rimonabant (a CB 1 receptor inverse agonist) were studied on antinociceptive responses following i.c. microinjections of improgan and the cannabinoid agonist WIN 55,212 (WIN) in rats. Separate intra-RM injections of improgan (30 μg) and WIN (8 μg) produced near-maximal antinociception on both the hot plate (HP) and tail flick (TF) nociceptive tests. Pretreatment with intra-RM rimonabant (20 μg) antagonized the antinociception produced by both intra-RM improgan and intra-RM WIN, but had no effects when given alone. Similar studies with improgan demonstrated rimonabant-sensitive sites within the dorsal and ventrolateral PAG. However, intra-RM pretreatment with rimonabant had no effect on antinociceptive responses following intra-PAG improgan. These studies show that improgan activates pain-relieving mechanisms in the PAG and the RM, both of which may utilize local cannabinoid mechanisms.

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Improgan-like Analgesics: A Family of Compounds Derived From Histamine Anatgonists

Cited by 6 publications

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Neural basis for improgan antinociception

Neural basis for improgan antinociception

Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia-Relevant Isoforms

Non-opioid antinociception produced by brain stem injections of improgan: Significance of local, but not cross-regional, cannabinoid mechanisms

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