Chronic pain affects one in three Americans. Socioeconomic costs attributed to inadequate pain management are estimated at $100 billion per year. The classic demonstration that analgesia can be elicited by environmental stressors provides evidence for endogenous pain inhibitory systems. Stress-induced analgesia is mediated in part by endogenous opioids. However, stress analgesia that is insensitive to blockade with opioid antagonists provides evidence for endogenous nonopioid analgesic systems. The mechanism underlying nonopioid stress-induced analgesia is completely unknown. Narrowing this gap is critical to harness the potential of endogenous nonopioid mechanisms for suppressing pain. The objective of this application is to identify the mechanism underlying nonopioid stress-induced analgesia. The central hypothesis is that environmental stressors release endocannabinoids -endogenous ligands for cannabinoid receptors- that suppress sensitivity to pain. The proposed research is expected to demonstrate that nonopioid stress-induced analgesia is: 1) blocked by a cannabinoid antagonist, 2) suppressed in rats rendered tolerant to cannabinoids, 3) attenuated by cannabinoid CB 1 antisense receptor knockdown, and 4) mediated by endogenous cannabinoids. The applicant is well-positioned to undertake this work because her research demonstrates that cannabinoids suppress pain neurotransmission and provides preliminary data that validates the central hypothesis. Completion of these aims is critical for establishing the biological significance of an endogenous cannabinoid transmitter system for suppressing pain. The proposed work is significant because the potential of nonopioid mechanisms for suppressing intractable pain cannot be realized until the underlying endogenous analgesic systems have been identify led. Pharmacological interventions that manipulate levels of endogenous cannabinoids by increasing synthesis and/or inhibiting inactivation represent novel targets for drug development. The development of effective pharmacotherapies for pain is likely to have a profound impact by driving down escalating health care costs and improving the quality of human life.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
5R03DA014265-02
Application #
6515910
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Thomas, David A
Project Start
2001-08-01
Project End
2004-05-31
Budget Start
2002-07-01
Budget End
2004-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$72,400
Indirect Cost
Name
University of Georgia
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
City
Athens
State
GA
Country
United States
Zip Code
30602
Suplita 2nd, Richard L; Eisenstein, Sarah A; Neely, Mark H et al. (2008) Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia. Neuropharmacology 54:161-71
Hohmann, A G (2007) Inhibitors of monoacylglycerol lipase as novel analgesics. Br J Pharmacol 150:673-5
Gutierrez, T; Farthing, J N; Zvonok, A M et al. (2007) Activation of peripheral cannabinoid CB1 and CB2 receptors suppresses the maintenance of inflammatory nociception: a comparative analysis. Br J Pharmacol 150:153-63
Hohmann, Andrea G; Suplita 2nd, Richard L (2006) Endocannabinoid mechanisms of pain modulation. AAPS J 8:E693-708
Connell, Katherine; Bolton, Nathan; Olsen, Daniel et al. (2006) Role of the basolateral nucleus of the amygdala in endocannabinoid-mediated stress-induced analgesia. Neurosci Lett 397:180-4
Suplita 2nd, Richard L; Gutierrez, Tannia; Fegley, Darren et al. (2006) Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia. Neuropharmacology 50:372-9
LoVerme, Jesse; Russo, Roberto; La Rana, Giovanna et al. (2006) Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha. J Pharmacol Exp Ther 319:1051-61
Hohmann, Andrea G; Neely, Mark H; Pina, Jeremiah et al. (2005) Neonatal chronic hind paw inflammation alters sensitization to intradermal capsaicin in adult rats: a behavioral and immunocytochemical study. J Pain 6:798-808
Nackley, A G; Zvonok, A M; Makriyannis, A et al. (2004) Activation of cannabinoid CB2 receptors suppresses C-fiber responses and windup in spinal wide dynamic range neurons in the absence and presence of inflammation. J Neurophysiol 92:3562-74
Hohmann, Andrea G; Farthing, Jesse N; Zvonok, Alexander M et al. (2004) Selective activation of cannabinoid CB2 receptors suppresses hyperalgesia evoked by intradermal capsaicin. J Pharmacol Exp Ther 308:446-53

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