Chronic Pain Addiction

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

[email protected]

(310)206-7883Thursday, February 14, 13

mailto:[email protected]





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)

Thursday, February 14, 13



Hedonic: Relating to the pleasurable affect of opioids

Analgesia: relating to the pain relieving attributes of opioids

Definitions




1. Opioids have analgesic and hedonic properties




• 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




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




2. Opioids are good pain relievers because of their

combined analgesic and hedonic properties




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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.




3. Opioids are less effective in chronic pain states, due in

part to changes in the hedonic system




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).




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




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




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.




4. In chronic pain, the motivation to take opioids is partly driven by analgesia




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




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




5. Opioid dependent states parallel chronic pain states




Cycle of opioid addiction

Addicts seek opioids to relievethe aversive state of withdrawal.

Chronic pain patients seek opioids to relieve the aversive

pain state.




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


- seek opioids to relieve pain - seek opioids to relieve withdrawal




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




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



- seek opioids to relieve pain - seek opioids to relieve withdrawal




Questions?

Anna Taylor, PhDHatos Center for Neuropharmacology

[email protected](310)206-7883




Chronic Pain Addiction

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