Neural basis for improgan antinociception

Abstract

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...

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

“…The holding temperature obviates any concern that apparent effects on reflex latency could be attributed to changes in skin temperature. Previous work has shown that response latencies and neuronal response properties are stable for a period of several hours with this testing protocol (Edelmayer et al 2009;Heinricher et al 2004Heinricher et al , 2010Kincaid et al 2006;Martenson et al 2009). …”

“…NEUTRAL-cells do not respond to improgan (Heinricher et al 2010) and remained unresponsive following CC12 pretreatment (n ϭ 5; data not shown).…”

“…We previously showed that improgan causes OFF-cells to become continuously active, with an increase in firing rate and elimination of the reflex-related pause. ON-cell firing is suppressed following icv improgan administration (Heinricher et al 2010).…”

“…Our experiments in anesthetized animals confirmed the broad function of CC12 as a central "analgesic antagonist," since both morphine and improgan antinociception were blocked by CC12 pretreatment. Because opioids, improgan, and cannabinoids all activate RVM OFF-cells (Heinricher and Ingram 2008;Heinricher et al 2010;Meng and Johansen 2004), one candidate mechanism for antagonism of the antinociceptive effect of all three drug classes was that CC12 suppresses firing of RVM OFF-cells or even all RVM neurons. This was ruled out in the present experiments, since CC12 had no effect on basal firing in RVM and failed to prevent the increase in spontaneous firing displayed by OFFcells following morphine and improgan.…”

“…Nevertheless, both drugs activate a physiologically defined population of RVM neurons, referred to as "OFF-cells," and suppress the firing of a second set, the "ON-cells" (Heinricher and Ingram 2008;Heinricher et al 2010). These two cell classes support bidirectional nociceptive modulation from the RVM: OFF-cells are defined by an abrupt cessation of activity ("OFF-cell pause") associated with nociceptive withdrawal responses, and these neurons have a net antinociceptive effect.…”