LINDSAY HOUGH

..A model is proposed in which (1) improgan activates an unknown receptor to trigger downstream P450 activity, and (2) brainstem epoxygenase activity is a point of convergence for opioid and nonopioid analgesic signaling...

..These studies show that improgan activates pain-relieving mechanisms in the PAG and the RM, both of which may utilize local cannabinoid mechanisms...

..Newer H(3) inverse agonists with potent, selective, and brain-penetrating properties show efficacy in several neuropathic and arthritis pain models, but the sites and mechanisms for these actions remain poorly understood...

..Elucidation of this mechanism will enhance understanding of the biochemistry of pain relief...

..SR141716A will facilitate the study of improgan-like analgesics...

..Since muscimol is the first compound discovered which inhibits improgan analgesia, muscimol will be a useful tool for the further characterization of this new class of pain-relieving substances...

..These studies demonstrate that improgan analgesia does not require intact MOR-1, DOR-1, or KOR-1 genes, and support the hypothesis that improgan-like analgesics act in the CNS by non-opioid mechanisms...

..Studies in progress are characterizing the sites and mechanisms of action of improgan, and developing brain-penetrating derivatives that could be useful for clinical pain...

..The sequestration of ibogaine by adipose tissue probably contributes to a protracted persistence of drug in the body. This persistence may be underestimated by the beta half-life reported in the present study...

..Although the mechanism of improgan antinociception remains unknown, the present results show promise for the further development of safe, effective, and potent pain-relieving compounds...

..The present results show that VUF5420 is a high potency, improgan-like, non-opioid analgesic which may indirectly activate cannabinoid pain-relieving mechanisms...

..These non-imidazole, improgan-like pain relievers further define the structural requirements for analgesics of this class and are important tools for ongoing mechanism-based studies...

..Thus, improgan produced highly effective analgesia without the development of tolerance...

..Like several other classes of analgesics, improgan-like drugs seem to activate non-opioid, descending pain-relieving circuits...

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..Unlike these other analgesics, improgan does not act in the spinal cord or in CNS areas outside of the brain stem...

..These results show no role for supraspinal cholinergic and 5-HT(3) receptors in improgan antinociception. The findings help to narrow the search for the relevant mediators of the action of this novel analgesic agent...

..These results will facilitate the judicious use of PPOH and MS-PPOH for epoxygenase research...

..The present study shows that drugs that stimulate H 3 receptors can reduce behavioral responses produced by some, but not all, painful stimuli. Thus, H 3 agonists could be a new type of therapy for certain kinds of pain disorders...

..Furthermore, these data suggest either a dissociation between seizures and thalamic lesions or a significant role of histamine in seizure-related damage to the thalamus...

..The present findings strongly support the hypothesis that neuronal histamine and its receptors fail to play a role in improgan-induced antinociception...

..Finally, CC12 is a new, potent inhibitor of CYP2B6 and CYP2C19 that may be a valuable tool for P450 research...

..Pharmacological stimulation of H3 receptors could be an important therapeutic approach for many disorders related to deep dermal or inflammatory pain...

..Improgan may use a marijuana-like (cannabinoid) pain-relieving mechanism, but it is shown presently that the principal cannabinoid receptor in the brain (CB(1)) is not solely responsible for improgan analgesia...

..Pretreatment with CC12 (183 microg, ivt) produced complete inhibition of both the antinociception and the hypothermia produced by improgan, suggesting the possible role of an unknown improgan receptor in both of these effects...

..Either possibility offers the potential for developing new types of analgesics...

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..These studies show that HNMT-S is a new mRNA species and putative protein product from HNMT. The physiological role of HNMT-S remains to be investigated...

..e. mechanical vs. thermal) inhibition of nociception by these receptors, and to assess the efficacy of spinally delivered histamine H(3) receptor agonists for the treatment for pain...

..Taken with recently published behavioral results, the present findings suggest that periarterial, peptidergic, H3R-containing A delta fibers may be sources of high threshold mechanical nociception...

..Although molecular studies have not yet identified the nature of this activity, the present work suggests that levels of biologically active histamine may be controlled by an extracellular process...

..This proposal will uncover new biochemical mechanisms for pain relief, and test a new group of chemicals for pain-relieving properties. This research could lead to the development of new, non-addicting pain relievers. ..

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..These experiments will help to discover the mechanism of action of this novel class of agents, and lead to the development of new pharmacotherapies for pain. ..

..These collaborative experiments between pharmacologists, neurophysiologists and chemists will discover the mechanism of action of this novel class of agents and lead to the development of new, non-opioid pharmacotherapies for pain. ..

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..These studies will enhance our knowledge of antinociceptive mechanisms, and may lead to the development of novel, clinically useful agents for the relief of pain...

..These studies will clarify the mechanisms by which MOR relieves pain, enhance the understanding of histaminergic antinociceptive mechanisms, and may lead to the discovery of non-addicting, novel medications for the treatment of pain. ..