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

Hough, Lindsay B.; Svokos, Konstantina; Nalwalk, Julia W.

doi:10.1016/j.brainres.2008.10.008

Cited by 11 publications

(10 citation statements)

References 39 publications

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“…This model incorporates earlier evidence that -opioid and cannabinoid receptor 1 (CB 1 ) agonists act presynaptically to inhibit GABA release from terminals mediating the OFF-cell pause (Heinricher et al 1991(Heinricher et al , 1992Meng and Johansen 2004;Pan et al 1990;Vaughan et al 1999) and that morphine engages an excitatory input to OFF-cells (Heinricher et al 2001b). It also brings together the observations that improgan, which lacks affinity for known cannabinoid receptors, produces antinociception dependent on CB 1 receptors (Hough et al 2009b;Nalwalk et al 2006) and that CC12 blocks antinociception produced by both CB 1 -receptor agonists and improgan (Hough et al 2007). Finally, taken together with recent evidence implicating P450 epoxygenase activity in -opioid analgesic action (Conroy et al 2010), the present findings with CC12 suggest a P450 link between presynaptic -opioid receptor activation and inhibition of GABA release onto OFF-cells. The model proposes that CC12 exerts its effects presynaptically, inhibiting an epoxygenase necessary for both opioid-and cannabinoid-induced inhibition of GABA release.…”

Section: An Epoxygenase Model For Opioid Cannabinoid and Improgan Amentioning

confidence: 68%

Physiological Basis for Inhibition of Morphine and Improgan Antinociception by CC12, a P450 Epoxygenase Inhibitor

Heinricher

Maire²,

Lee³

et al. 2010

Journal of Neurophysiology

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Heinricher MM, Maire JJ, Lee D, Nalwalk JW, Hough LB. Physiological basis for inhibition of morphine and improgan antinociception by CC12, a P450 epoxygenase inhibitor. J Neurophysiol 104: 3222-3230, 2010. First published October 6, 2010 doi:10.1152/jn.00681.2010. Many analgesic drugs, including -opioids, cannabinoids, and the novel nonopioid analgesic improgan, produce antinociception by actions in the rostral ventromedial medulla (RVM). There they activate pain-inhibiting neurons, termed "OFF-cells," defined by a nociceptive reflex-related pause in activity. Based on recent functional evidence that neuronal P450 epoxygenases are important for the central antinociceptive actions of morphine and improgan, we explored the convergence of opioid and nonopioid analgesic drug actions in RVM by studying the effects of the P450 epoxygenase inhibitor CC12 on the analgesic drug-induced activation of these OFF-cells and on behavioral antinociception. In rats lightly anesthetized with isoflurane, we recorded the effects of intraventricular morphine and improgan, with and without CC12 pretreatment, on tail flick latency and activity of identified RVM neurons: OFF-cells, ON-cells (pronociceptive neurons), and NEUTRAL cells (unresponsive to analgesic drugs). CC12 pretreatment preserved reflex-related changes in OFF-cell firing and blocked the analgesic actions of both drugs, without interfering with the increase in spontaneous firing induced by improgan or morphine. CC12 blocked suppression of evoked ON-cell firing by improgan, but not morphine. CC12 pretreatment had no effect by itself on RVM neurons or behavior. These data show that the epoxygenase inhibitor CC12 works downstream from receptors for both -opioid and improgan, at the inhibitory input mediating the OFF-cell pause. This circuit-level analysis thus provides a cellular basis for the convergence of opioid and nonopioid analgesic actions in the RVM. A presynaptic P450 epoxygenase may therefore be an important target for development of clinically useful nonopioid analgesic drugs.

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Section: An Epoxygenase Model For Opioid Cannabinoid and Improgan Amentioning

confidence: 68%

Physiological Basis for Inhibition of Morphine and Improgan Antinociception by CC12, a P450 Epoxygenase Inhibitor

Heinricher

Maire²,

Lee³

et al. 2010

Journal of Neurophysiology

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“…The best studied opioid-sensitive descending system has critical links in the periaqueductal gray and rostral ventromedial medulla (RVM). In recent extensive mapping studies, improgan was shown to act in both sites (Hough et al, 2001; Nalwalk et al, 2004; Hough et al, 2009). Further, the antinociceptive effect of icv improgan is abolished by functional lesions of the RVM, showing an essential requirement for activation of RVM neurons in the antinociceptive actions of improgan (Nalwalk et al, 2004).…”

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confidence: 99%

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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“…Presently, DMSO was used to dissolve CC44 in some experiments, but it is unlikely that use of this solvent invalidated the present conclusions. For example, published (Hough et al, 2009 vs. Nalwalk et al, 2004; Hough et al, 2002 vs. Hough et al, 2006) and unpublished studies from our lab found no differences in analgesic potency for improgan dissolved in saline as compared with DMSO. In addition, CC44 (i.c.v.)…”

Section: Discussionmentioning

confidence: 66%

Antinociceptive activity of CC44, a biotinylated improgan congener

Hoerbelt

Nalwalk

Phillips³

et al. 2013

European Journal of Pharmacology

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Improgan, a non-opioid, antinociceptive drug, activates descending analgesic circuits following brain administration, but the improgan receptor remains unidentified. Since biotinylation of drugs can enhance drug potency or facilitate discovery of new drug targets, a biotinylated congener of improgan (CC44) and several related compounds were synthesized and tested for antinociceptive activity. In rats and mice, intracerebroventricular (i.c.v.) administration of CC44 produced dose-dependent reductions in thermal nociceptive (tail flick and hot plate) responses, with 5-fold greater potency than improgan. CC44 also robustly attenuated mechanical (tail pinch) nociception in normal rats and mechanical allodynia in a spinal nerve ligation model of neuropathic pain. Similar to the effects of improgan, CC44 antinociception was reversed by the GABAA agonist muscimol (consistent with activation of analgesic circuits), and was resistant to the opioid antagonist naltrexone (implying a non-opioid mechanism). Also like improgan, CC44 produced thermal antinociception when microinjected into the rostral ventromedial medulla (RVM). Unlike improgan, CC44 (i.c.v.) produced antinociception which was resistant to antagonism by the cannabinoid CB1 antagonist/inverse agonist rimonabant. CC44 was inactive in mice following systemic administration, indicating that CC44 does not penetrate the brain. Preliminary findings with other CC44 congeners suggest that the heteroaromatic nucleus (imidazole), but not the biotin moiety, is required for CC44’s antinociceptive activity. These findings demonstrate that CC44 is a potent analgesic compound with many improgan-like characteristics. Since powerful techniques are available to characterize and identify the binding partners for biotin-containing ligands, CC44 may be useful in searching for new receptors for analgesic drugs.

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

Cited by 11 publications

References 39 publications

Physiological Basis for Inhibition of Morphine and Improgan Antinociception by CC12, a P450 Epoxygenase Inhibitor

Physiological Basis for Inhibition of Morphine and Improgan Antinociception by CC12, a P450 Epoxygenase Inhibitor

Neural basis for improgan antinociception

Antinociceptive activity of CC44, a biotinylated improgan congener

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