chronic pain addiction
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7/28/2019 Chronic Pain Addiction
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Opioids and chronic pain:
the balance between pain relief and addiction
Neuroscience C177:
Drugs of abuse from neurobiology to policy and education
Anna Taylor, PhD
Hatos Center for Neuropharmacology
ataylor1@ucla.edu
(310)206-7883Thursday, February 14, 13
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CHRONIC PAIN
Neuropathic Inflammatory Idiopathic•trauma
•surgery
•diabetic neuropathy
•arthritis
•visceral pain•migraine
•fibromyalgia
Chronic pain leads to neuropathological adaptation within the peripheral and central nervous system that causes
dysregulation of the pain signal. this includes hyper excitability of nociceptive pathways, loss of internal inhibitory
control, and general inflammation of the central nervous system (glial activation)
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Hedonic: Relating to the pleasurable affect of opioids
Analgesia: relating to the pain relieving attributes of opioids
Definitions
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1. Opioids have analgesic and hedonic properties
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• The ventral tegmental area (VTA) is a brainnuclei within the mesolimbic system(meso=mid brain, limbic=striatum) that containsdopaminergic cell bodies.
• Opioids act here to increase dopamine release by inhibiting the inhibition of GABAergic
interneurons acting on dopaminergic neurons(Disinhibition)
Hedonic mechanisms of opioids
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Analgesic mechanisms of opioids
Opioid receptors are distributed widely throughout the peripheral
and central nervous system, and contribute to analgesia.
Periphery and spinal cord:
Opioids binding to mu opioid receptors on pain specific primary
afferents, called “nociceptors” in the skin and spinal cord directly
inhibit the pain signal.
Brain Ascending pathways:
Opioid receptors are also distributed throughout the brain regionsinvolved in pain processing, called the “pain matrix”. These brain
regions include the thalamus, sensory cortex, and amygdala. Opioids
acting at these receptor further inhibit the pain signal.
Brain Descending pathways:
Opioid receptors are also located in the descending noxious
inhibitory control (DNIC) pathway, that represents the internal
“brake” on the pain sensation. Brain regions include the
rostroventral medulla and the periaquaductal grey, and activation of this pathway inhibits the pain signal at the level of the spinal cord.
Distribution of opioid receptors in these brain regions is such that
opioids directly activate DNIC signaling, adding a further dimension
to opioids ability to inhibit pain.DH=dorsal horn, DRG, dorsal root ganglia, DRN = Dorsal raphe nucleus,
HY=hypothalamus, IC= insular cortex, NRM= nucleus raphe magnus,
NAc-nucleus accumbens, PAG=periaqueductal grey
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2. Opioids are good pain relievers because of their
combined analgesic and hedonic properties
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90 1~3 LESIONS
70
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SA LINE D-AMPH D-AMPH1.5 mg/kg 3.0 mg/kg
100- 1"-'3 SHAMS
~'~ LESIONS80. i
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[rSALINE MO RP HIN E MORPHINE3.0 mg/kg 6.0 mg/k g
FIG. 2. The analgesic effect of amphetamine and morphine in rats with
6-hydroxydopamine-induced lesions of the ventral tegmental dopaminecells or with sham lesions (0.05% ascorbic acid vehicle). In sham-lesionedrats both morphine and amphetamine produced significant (.0<0.05)
Lesion of the mesolimbic dopamine system reduces opioid
analgesia
Injection of low dose of formalin intothe hind paw of the mouse results in alocalized inflammatory state that isaccompanied by a persistent painsensation. The level of analgesia can be
measured by testing paw withdrawalthresholds of thermal or mechanicalstimuli (graphed here as a percentage).Specific lesions of the VTA
significantly reduced morphine
analgesia.
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3. Opioids are less effective in chronic pain states, due in
part to changes in the hedonic system
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How to measure “reward” in non-communicatinganimals
Self-administration
Animals are implanted with an intravenous catheter (usually) connected to a reservoir of drug. Animalsare confined to an operant box with 1-2 levers available to press. Over time, animals will learn that
pressing the active lever will lead to infusion of drug. If the drug is rewarding, the animal will pressthe lever more and more. In order to further probe drug reward, you can make the animal have to work
harder to receive the drug infusion. For example, they may have to press the lever 3 times (Fixed Ratio3, FR3) to receive one drug infusion rather than just once (FR1).
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How to measure “reward” in non-communicatinganimals
Conditioned place preference
A 2 (or sometimes 3) chambered apparatus is used. The two chambers are distinguished from oneanother with different sensory cues (patterned walls, textured floors), and are connected by a door.During 8 conditioning sessions, animals are confined to one chamber or the other on alternating daysfor 20-30 minutes, and receive either drug or saline injection. Over time, the animal learns to associatethe drug sensation with a specific chamber. On the final post conditioning day, animals are placed in theapparatus, and the door connecting the two chambers is opened, allowing the animal access to bothchambers. The time spent in the drug paired chamber is measured. Drugs that are rewarding should
cause the animal to spend more time in the “drug paired” side.
Drug
SalinePost conditioning Day
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Opioid self administration is reduced inchronic pain animals, when comparedto sham (non pain) controls. Only highdoses of opioids which are analgesic,are self administered at normal levels
The reward system is disrupted in chronic pain
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The reward system is disrupted in chronic pain
Neurotransmitter release is measured
in awake, behaving animals by
microdialysis. A microdialysis probe
is inserted into the brain region of
interest (in this case, ventral striatum).
The tip of the probe is formed of asemi-permeable membrane that
allows passage of neurotransmitter
from the extracellular space into the
probe. Samples are collected and run
through HPLC to measure levels of
neurotransmitter in the sample before
and after drug administration.
Morphine fails to stimulate
dopamine release in the nucleusaccumbens of chronic pain animals.
Cocaine response is preserved,
suggesting chronic pain states have
a specific desensitization to opioids.
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4. In chronic pain, the motivation to take opioids is partly driven by analgesia
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If you relieve the pain with a non-rewarding analgesic drug (clonidine),
opioid self-administration is decreased inchronic pain states. Clonidine has noeffect in shams (non-pain controls) onopioid self administration
Relief of pain decreases opioid self administration
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If you relieve the pain with a non-rewarding analgesic drug (lidocaine directly onthe injured peripheral nerve or intrathecal clonidine) you can block opioid place
preference as well in chronic pain (SNL=spinal nerve ligation) but not shamcontrols
8 conditioning sessions 2 conditioning sessions
Relief of pain induces conditioned place preference
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5. Opioid dependent states parallel chronic pain states
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Cycle of opioid addiction
Addicts seek opioids to relievethe aversive state of withdrawal.
Chronic pain patients seek opioids to relieve the aversive
pain state.
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Parallels between opioid dependence and chronic
pain
Chronic pain Opioid dependence
- high levels of circulating endogenous opioids - chronic opiate exposure
- lowered analgesic efficacy - tolerance
- glial activation/inflammation - glial activation/inflammation
- lowered dopamine release in the striatum inresponse to opioids
- lowered dopamine release in the striatum inresponse to opioids
- seek opioids to relieve pain - seek opioids to relieve withdrawal
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Glial activation in chronic pain and opioid dependence
Sham
Chronic Pain
Chronic pain and prolonged
opioid exposure leads to glialactivation (inflammation)
throughout the brain. Thisglial activation directlyaffects excitability of
surrounding neurons, and
contributes to theneurological adaptation
associated with pathology
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Parallels between opioid dependence and chronic
pain
Chronic pain Opioid dependence
- high levels of circulating endogenous opioids - chronic opiate exposure
- lowered analgesic efficacy - tolerance
- glial activation/inflammation - glial activation/inflammation
- lowered dopamine release in the striatum inresponse to opioids
- lowered dopamine release in the striatum inresponse to opioids
- seek opioids to relieve pain - seek opioids to relieve withdrawal
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Questions?
Anna Taylor, PhDHatos Center for Neuropharmacology
ataylor1@ucla.edu(310)206-7883
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