Anesthesiology & Pain Medicine >> Research >> Focus Areas >> Pain Medicine & Neuroscience >> Modulation of Pruritus by Spinal Cannabinoids
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Research Focus Areas:
Pain Medicine & Neuroscience

Modulation of Pruritus by Spinal Cannabinoids

Principal Investigators

G. W. Terman, M.D., Ph.D.

Description

For the last several years my laboratory has studied the neurochemical changes that take place in the neonatal rat spinal cord following repeated opiate administration as a cellular model of opiate analgesic tolerance. We have reported NMDA receptor-mediated increases in nociceptive primary afferent synaptic transmission associated with opiate tolerance. We have also discovered that the endocannabinoid 2-arachidonoylglycerol (2-AG), released in response to increased nociceptor activity, feeds back to inhibit such activity by acting at presynaptic CB1 receptors. Recently, we found that, like nociception, itch sensation, also appears to be increased in animals previously exposed to repeated morphine injections, although this effect is largely masked by concurrent spinal endocannabinoid inhibition. After intrathecal adminstration of the CB1 receptor antagonist SR141716 (SR) significant increases in scratching behaviors are observed — particularly in rats previously treated with repeated morphine injections. We hypothesize that repeated opiate administration induces central sensitization of primary afferent neurotransmission of pruritus, thereby increasing the synthesis and release of 2-AG, which in turn feeds back to inhibit itch by binding to presynaptic CB1 receptors. The current application proposes to begin testing this hypothesis with two specific aims:

  1. To verify that spinal endocannabinoids act at spinal CB1 receptors to inhibit itch.
    To test this belief, we will intrathecally inject a different CB1 antagonist (AM251) and a 2-AG synthesizing enzyme (DAG lipase) inhibitor to study whether these means of inhibiting spinal 2-AG effects can also increase scratching behaviors in neonatal rats. We will also use immunocytochemistry to ascertain that, as in adults, both CB1 receptors and DAG lipase are present in the dorsal horn of neonatal rats. Finally, we will attempt to replicate and extend our intrathecal SR studies to adult mice and compare these effects with those in littermate CB1 receptor knockout mice.
  2. To investigate the mechanism by which anti-pruritic endocannabinoids are released in the spinal cord.
    Our data suggest that following repeated morphine injections not only are nociceptive primary afferents more active but primary afferents related to itch are also more excitable. We have previously found that morphine-induced primary afferent nociceptor sensitization is mediated predominately via NMDA receptors. In these studies we will test whether opiate-induced sensitization to itch is also mediated by NMDA receptors and can be inhibited by the NMDA receptor antagonist MK801. Further we will use Gastrin Releasing Peptide (GRP) to study whether application of this peptide, recently reported to produce spinally-mediated pruritus, causes endocannabinoid release as evidenced by SR-induced increases in scratching in vivo and/or spinal dorsal horn EPSC frequency in vitro.

Such studies may suggest novel anti-pruritic therapies for cannabinoids as well as providing new models and concepts to investigate the neural underpinnings of spinal interactions between pain and itch.

Pain Medicine & Neuroscience:
Research Projects

An Internet CBT Intervention for Pediatric Chronic Pain and Disability
T. Palermo, Ph.D.
Cervical Sympathetic Block in Patients with Cerebral Vasospasm following Aneurysmal Subarachnoid Hemmorhage
M. DePinto, M.D., M.M. Treggiari, M.D., Ph.D., M.P.H.
Controlling Pain After Trauma
D. Patterson, Ph.D., S. R. Sharar, M.D., M. Jensen, Ph.D., H. Hoffman, Ph.D., et al.
Cytokine and Neurotransmitter Interactions in Sleep Regulation
M. R. Opp, Ph.D., L. Imeri, M.D.
Disability from Pediatric Traumatic Brain Injury
P Rivara, M.D., M. S. Vavilala, M.D.
Drug Interactions at the Human Blood-Brain Barrier
J. D. Unadkat, Ph.D., K. B. Domino, M.D., M.P.H., A. Collier, M.D., et al.
Effectiveness of Oxymorphone for Acute Postoperative Pain Pediatric Subjects
S.Bhananker, M.D.
Identifying Virtual Reality Analgesia Mechanisms by Pharmacologic Manipulation
S. R. Sharar, M. D., D.A. Patterson, Ph.D, H.Hunter, Ph.D., et al.
Influence of Dexmedetomidine on the Evoked Potentials During Spine Surgery
Rozet, M.D.
Innovations In Pediatric Pain Research
T. Palermo, Ph.D.
Ketorolac in Surgical Infants: Pharmacokinetics/Analgesia
A.M. Lynn, M.D.
Mechanism Of Action Of Volatile Anesthetics
P.G. Morgan, M.D.
Memantine for Post-Operative Pain Control in the Opiate-Tolerant Patient
G. Terman, M.D., Ph.D.
Modulation of Pruritus by Spinal Cannabinoids
G. W. Terman, M.D.,Ph.D.
Molecular Mechanisms of Sleep Responses to Viral Infection
James Krueger, PhD (WSU: PI); Mark R. Opp, PhD (co-investigator/subcontract PI)
Neonatal Pain, Depression and Pain Susceptibility at Maturity in Rats
Gayle Page, DNSc, RN (Johns Hopkins: PI); Mark R. Opp, PhD (co-investigator/subcontract PI)
Neurologic Injury after Non-Supine Surgery Registry
L. A. Lee, M.D., L. Stephens, Ph.D., K. B. Domino, M.D., M.P.H., K. L. Posner, Ph.D.
Neuron-glial communication and brain aging
Paula Bickford, PhD (University of South Florida: PI); Carmelina Gemma, PhD (co-investigator/subcontract PI)
Neuronal-Glial Dialogue and Cognition
Carmelina Gemma, PhD (PI)
Neurotoxic Effects of Volatile Anesthetics in C. Elegans
P.G. Morgan, M.D.
Open Label Study of the Safety and Efficacy of Conivaptan (Vaprisol) to raise serum sodium levels in patients with severe traumatic brain injury
M. M. Treggiari, M.D., Ph.D., M.P.H., S. A. Deem, M.D., N.D. Yanez III, Ph.D.
Optimizing the Control of Pain from Severe Burns
D. Patterson, Ph.D.; S R. Sharar, MD; D. Heimbach, MD., J Doctor, Ph.D.
Patient Perceptions of the Benefits of Long-Term Opioid Therapy (PLOT) Initiative-Beliefs and Behaviors
D. C. Turk, Ph.D., J. P. Robinson., M.D., R. Landau, M.D.
Sepsis Outcomes and Aging: Role of Sleep Disruption and the Blood Brain Barrier
Mark R. Opp, PhD (PI); William A. Banks, MD (co-investigator); Richard M. Raymond, PhD (co-investigator)
Shared Decision Making in Orthopaedic Spine Surgery to Improve Patient Safety
K. B. Domino,M.D, M.P.H.; K. L. Posner, Ph.D. et al.
Sleep-Wake Disturbances in Adolescents with Chronic Pain Research
T. Palermo, Ph.D.
Subgroups of FMS: Symptoms, Beliefs & Tailored Treatments
D.C. Turk, Ph.D., J. Robinson, M.D., Ph.D.
Subjective and Neuroimaging Assessment of Combined Opioid and Virtual Reality Analgesia
S. R. Sharar, M.D., T. Richards, Ph.D.
Ultrasound Guided Rectus Sheath Block for Post-Operative Pain Control Following Umbilical Hernia Repair
S. Flack, M.D.
University of Washington Urologic Chronic Pelvic Pain Syndromes Discovery Center
D. S. Buchwald, M.D., N. Jimenez, M. D., et al.
Web-based CBT for Opioid-treated Chronic Pain Patients With Aberrant Behavior
Rosenblum, Ph.D., D.C. Turk, Ph.D.