1995 — 1999 |
Wiertelak, Eric P |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Central Hyperalgesia Systems and Analgesic Efficacy
It is well known that the CNS contains opiate and non-opiate circuitry that acts to inhibit pain via production of analgesia. This circuitry can be activated by aversive or stressful stimuli, or environmental cues that predict impending exposure to such stimulation. Our recent evidence suggests hyperalgesia mechanisms may increase pain sensitivity in a manner complementary to analgesia mechanism activity: 1)Just as analgesia can be activated by exposure to a stressful or aversive external stimulus, central hyperalgesia mechanisms can be activated by acute exposure to an aversive internal stimulus. An aversive internal state is produced through intraperitoneal (IP) injection of lithium chloride (LiCl) or lipopolysaccharides (Endotoxin), which induce a potent cutaneous hyperalgesia as measured by the tailflick test of pain sensitivity. 2) Just as animals can learn to become analgesic in response to environmental cues that predict impending stressful or aversive external stimulation (conditioned analgesia), animals can learn to activate central mechanisms to become hyperalgesic in response to cues that predict impending internal aversive stimulation (conditioned hyperalgesia). A cue for an impending internal aversive state (emesis) was established by repeatedly pairing a novel taste with IP LiCl (conditioned taste aversion). 3)Endogenous opiates are implicated in the mediation of both the acute and learned forms of this hyperalgesia, as systemic naltrexone reverses the effect. The possibility that environmental stressors, cues for such, or analgesic agents such as the opiates may result in the simultaneous activation of both pain inhibitory and pain facilitory mechanisms has clinical implications. An understanding of these hyperalgesia systems and how they might interact with pain inhibitory processes could lead to the development of novel approaches for the control of pain and treatment of addiction. The aim of this proposal is to investigate: 1)the endogenous mechanisms underlying these central hyperalgesia systems, and 2) the possible impact of hyperalgesia system activation on the pain inhibition or analgesic efficacy produced in conditioned analgesia and acute morphine analgesia paradigms. CNS pharmacology (intrathecal and intracerebroventricular microinjection studies), lesion (electrolytic and excitotoxic lesions of specific brain sites), and behavior studies will be conducted to address basic, well defined issues central to the understanding and characterization of the mechanisms of this newly discovered circuitry.
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2005 |
Wiertelak, Eric P |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Impact of Cholinergic Plant Extracts On Nociception
DESCRIPTION (provided by applicant): This study is an initial investigation into the traditional (folk) medicine practice of using Solenace plants for pain relief. Solenace plants that will be investigated include: Atropa belladonna, Datura Stramonium, Mandragoras officinarum, Hyoscyamos niger and Solanum nigrum; each have documented use for pain relief in folk medicine. The psychoactive properties of these plants are largely attributed to concentrations of anticholinergic tropane alkaloids such as atropine, scopolamine, hyoscyamine, hyoscine and atroscine. In order to investigate the application of extracts from Solenace plants for pain relief, rat pain models will be employed, which will allow for assessment of the efficacy of these plants for pain relief beyond folk applications. Solenace plant extracts will be produced and analyzed to identify and quantify alkaloids and to determine dose-response characteristics of any alkaloid derived pain alterations. In addition to systemic, the effects of intrathecal extract administrations will be tested in three pain paradigms: hot-plate, tail-flick, and formalin tests, as spinal cholinergic circuitry has been implicated in pain responsivity. Extract and alkaloid induced alterations in pain responsivity will also be tested in animals receiving lesions of the rostral ventrpmedial medulla, a key supraspinal pain locus featuring dense muscarinic cholinergic innervation. This study will also examine the pain alterations caused by non-cholinergic hallucinogens, to determine whether changes in pain responsivity seen caused by extracts and alkaloids result from their hallucinogenic properties. Based on the results of these studies, a further investigation will focus on the development of new assays that test aspects of pain responsivity that may not be assessed by current paradigms. Together, the proposed studies will provide specific information regarding the viability, effects, and routes of action of extracts from Solenace plants in analgesic applications, and may contribute to the development of novel treatments for pain relief in humans.
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