The neurobiological basis of pain and the neural circuits that underlie pain perception and pain inhibition remain fundamental problems for neuroscientists. Much research in the past 25 years has focused on mechanisms in the brain that modulate pain sensitivity, especially those mechanisms related to the neurotransmitters and neuromodulators that control acute and chronic pain. Marijuana has been used for pain relief for centuries, but only recently has the mechanism of its actions on the neural processing of painful inputs been studied. Cannabinoids depress the reaction of nociceptive neurons in the spinal cord, lateral and medial thalamus. This action takes place by effects of cannabinoids on specific brain structures, the spinal cord, and the peripheral nerve itself. Besides depressing acute or nociceptive pain, cannabinoids are active in models of chronic pain, inflamation neuropathic pain and in an electrophysiological model of windup. Virtually nothing is known about the neuronal mechanisms of cannabinoid suppression of the pathological pain produced by nerve injury, which is the subject of this renewal application. The proposed experiments examine the effects of a cannabinoid agonist on pain behavior and spinal neural processing of tactile inputs in rats with chronic constriction injury of the sciatic nerve. The proposed studies further examine the effects of a cannabinoids on abnormally high levels of spontaneous discharge, the hyper excitability of mild and noxious mechanical stimuli and responses to stimulation of different peripheral fiber types. Pharmacological specificity will be examined using selective CB1 and CB2 cannabinoid receptor antagonists. These studies may shed light on the actions of endogenous cannabinoids in chronic pain because any effects of a cannabinoid antagonist that is opposite to that of an agonist may be the result of blockade of an endogenous modulator of the cannabinoid receptor. The sites of action of the drug will be examined in studies in which the compounds are applied locally to a specific brain region (the dorsal periaquductal gray), the spinal cord, the dorsal root ganglion or at the site of injury. The results of these studies will reveal mechanisms by which cannabinoids modulate the pathological pain, and suggests future studies directed at determining the role of endocannabinoids in pain processing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033247-05
Application #
6188118
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (03))
Program Officer
Kitt, Cheryl A
Project Start
1995-05-01
Project End
2004-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
5
Fiscal Year
2000
Total Cost
$254,930
Indirect Cost
Name
Brown University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Bradshaw, Heather B; Walker, J Michael (2005) The expanding field of cannabimimetic and related lipid mediators. Br J Pharmacol 144:459-65
Breivogel, Christopher S; Walker, J Michael; Huang, Susan M et al. (2004) Cannabinoid signaling in rat cerebellar granule cells: G-protein activation, inhibition of glutamate release and endogenous cannabinoids. Neuropharmacology 47:81-91
De Petrocellis, Luciano; Chu, Constance J; Moriello, Aniello Schiano et al. (2004) Actions of two naturally occurring saturated N-acyldopamines on transient receptor potential vanilloid 1 (TRPV1) channels. Br J Pharmacol 143:251-6
Fernandez-Rodriguez, Conrado M; Romero, Julian; Petros, Timothy J et al. (2004) Circulating endogenous cannabinoid anandamide and portal, systemic and renal hemodynamics in cirrhosis. Liver Int 24:477-83
Chu, Constance J; Huang, Susan M; De Petrocellis, Luciano et al. (2003) N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia. J Biol Chem 278:13633-9
Huang, Susan M; Bisogno, Tiziana; Trevisani, Marcello et al. (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci U S A 99:8400-5
Burstein, Sumner H; Huang, Susan M; Petros, Timothy J et al. (2002) Regulation of anandamide tissue levels by N-arachidonylglycine. Biochem Pharmacol 64:1147-50
Huang, S M; Bisogno, T; Petros, T J et al. (2001) Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits pain. J Biol Chem 276:42639-44
Sanudo-Pena, M C; Tsou, K; Romero, J et al. (2000) Role of the superior colliculus in the motor effects of cannabinoids and dopamine. Brain Res 853:207-14
Sanudo-Pena, M C; Romero, J; Seale, G E et al. (2000) Activational role of cannabinoids on movement. Eur J Pharmacol 391:269-74

Showing the most recent 10 out of 34 publications