Opioid and cannabinoid interactions in pain and reward

Abstract
Chronic pain is a significant public health problem that costs society billions of dollars per year and causes great
suffering in countless individuals. Opioid-based medications are among the most prescribed for various forms of
chronic pain contributing to the current opioid epidemic. Recently, cannabis and cannabinoid compounds (e.g.,
Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD)) have been described as having pain-alleviating
properties. While these cannabinoids, particularly the less psychoactive variant, CBD, may offer alternatives to
opioid treatments for pain, few well-controlled studies demonstrate analgesic efficacy, especially for CBD. While
it is still unclear if cannabinoids are good stand-alone options for treating pain, cannabinoids may act as useful
opioid-sparing drugs, given the substantial overlap between opioid and cannabinoid receptors in reward- and
pain-related pathways. Our proposed project will focus on a heuristic approach that incorporates fundamental
pharmacology, novel operant behavioral assays of pain, and functional neuroimaging. The long-term goal of
this research program is to establish novel approaches to treat chronic pain by maximizing analgesic efficacy
and minimizing abuse liability. The objective of this proposal, which embodies the first step toward this long-
term goal, is to determine how CBD modifies the effects of oxycodone (OXY), a commonly prescribed opioid
analgesic, in the contexts of chronic pain and opioid self-administration. Our overarching hypothesis is that
CBD and OXY will act synergistically to yield enhanced analgesic effects, and that CBD will attenuate the effects
of pain on OXY self-administration. Two major specific aims will be investigated: (1) to determine how CBD
interacts with OXY to reduce chronic operant pain behaviors; and (2) to determine the interacting effects
of chronic pain, OXY self-administration, and CBD on analgesia, reinforcement, and dependence. We will
assess the effects of preexisting pain on OXY self-administration, as well as the effects of preexisting OXY self-
administration on pain. The latter goal is a particularly innovative aspect of this proposal. CBD-modulatory effects
on pain and OXY self-administration will be evaluated under both conditions. Neuroimaging will be used across
experiments to map and quantify changes in neural connectivity across reward and pain centers of the brain
following the various drug treatments (CBD, OXY) and pain states (acute, chronic). Further, we will use clinically
important and innovative pain-depressed behavioral assessments that accurately model pain in human subjects.
The rationale for completing these studies is that by determining how CBD and OXY interact to affect pain and
substance use, we will establish the necessary foundation for future efforts to develop effective analgesics with
reduced abuse liability. We believe we are particularly well suited to undertake this project because we have a
unified (and already collaborating) multidisciplinary team with complementary expertise in behavioral
neuroscience, pharmacology, and neuroimaging.

Grant Number: 5R01DA049470-05
NIH Institute/Center: NIH
Principal Investigator: ROBERT CAUDLE