Cannabinoids, which include the major psychoactive ingredient in marijuana, delta-9-tetrahydrocannabinol, have a long history of use for the treatment of pain. The mechanisms by which cannabinoids may reduce pain, however, remain largely unexplored. This proposal is focused on the mechanisms of cannabinoid inhibition of nociceptive signals relevant to head and face pain. The medullary dorsal horn receives nociceptive input from orofacial regions, and as the first site of neuronal integration represents a potentially critical target for the antinociceptive actions of cannabinoids. Behavioral experiments have demonstrated that intrathecal administration of a kappa opioid receptor antagonist blocks the antinociceptive effect of intrathecally administered cannabinoids, suggesting that inhibition of nociceptive signals produced by cannabinoid agonists require the release of an endogenous kappa opioid receptor agonist. The proposed experiments will compare the effect of cannabinoids on nociceptive neurons located in superficial versus deep laminae of the medullary dorsal horn. Furthermore, we will determine whether cannabinoids produce inhibition of medullary dorsal horn nociceptive neurons indirectly by stimulating the release of an endogenous kappa opioid receptor agonist. Using extracellular electrophysiological single unit recordings, we will compare the effect of cannabinoid receptor agonists applied directly to the medullary dorsal horn (bath application) on the activity of superficial and deep nociceptive neurons. Neuronal activity will be evoked by thermal stimulation of the receptive field. Stimulus response functions will be compared both prior to and following bath application of cannabinoid agonists. To determine whether cannabinoids indirectly modulate neuronal activity by inducing the release of an endogenous kappa opioid receptor agonist, cannabinoids will be tested in the presence of a kappa opioid receptor antagonist. Finally, the effect of a kappa opioid receptor agonist (bath application) on heat evoked activity of medullary dorsal horn neurons will be examined to allow for a direct comparison with kappa opioid receptor sensitive cannabinoid effects. The long-term objective of this research is to increase our understanding of the neuropharmacological mechanisms underlying cannabinoid-induced suppression of trigeminal pain and ultimately determine whether cannabinoids may be a useful class of medication for trigeminal pain patients as either a primary or adjuvant therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014548-04
Application #
6913409
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Thomas, David A
Project Start
2002-08-15
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2007-05-31
Support Year
4
Fiscal Year
2005
Total Cost
$187,454
Indirect Cost
Name
University of New England
Department
Physiology
Type
Schools of Osteopathy
DUNS #
071735252
City
Biddeford
State
ME
Country
United States
Zip Code
04005
Harasawa, Ichiro; Johansen, Joshua P; Fields, Howard L et al. (2016) Alterations in the rostral ventromedial medulla after the selective ablation of ?-opioid receptor expressing neurons. Pain 157:166-73
Robbins, Ashlee; Schmitt, David; Winterson, Barbara J et al. (2012) Chronic morphine increases Fos-positive neurons after concurrent cornea and tail stimulation. Headache 52:262-73
Reynolds, Jacques; Bilsky, Edward J; Meng, Ian D (2011) Selective ablation of mu-opioid receptor expressing neurons in the rostral ventromedial medulla attenuates stress-induced mechanical hypersensitivity. Life Sci 89:313-9
Okada-Ogawa, Akiko; Kurose, Masayuki; Meng, Ian D (2010) Attenuation of cannabinoid-induced inhibition of medullary dorsal horn neurons by a kappa-opioid receptor antagonist. Brain Res 1359:81-9
Ogawa, Akiko; Meng, Ian D (2009) Differential effects of the cannabinoid receptor agonist, WIN 55,212-2, on lamina I and lamina V spinal trigeminal nucleus caudalis neurons. Pain 141:269-75
Okada-Ogawa, Akiko; Porreca, Frank; Meng, Ian D (2009) Sustained morphine-induced sensitization and loss of diffuse noxious inhibitory controls in dura-sensitive medullary dorsal horn neurons. J Neurosci 29:15828-35
Ogawa, A; Meng, I D (2006) The cannabinoid receptor agonist, WIN 55,212-2, inhibits cool-specific lamina I medullary dorsal horn neurons. Neuroscience 143:265-72
Meng, I D; Johansen, J P; Harasawa, I et al. (2005) Kappa opioids inhibit physiologically identified medullary pain modulating neurons and reduce morphine antinociception. J Neurophysiol 93:1138-44
Papanastassiou, Alex M; Fields, Howard L; Meng, Ian D (2004) Local application of the cannabinoid receptor agonist, WIN 55,212-2, to spinal trigeminal nucleus caudalis differentially affects nociceptive and non-nociceptive neurons. Pain 107:267-75
Meng, I D; Johansen, J P (2004) Antinociception and modulation of rostral ventromedial medulla neuronal activity by local microinfusion of a cannabinoid receptor agonist. Neuroscience 124:685-93

Showing the most recent 10 out of 11 publications