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)206-7883
Thursday, February 14, 13

CHRONIC PAIN

Neuropathic
trauma surgery diabetic neuropathy

Inflammatory
arthritis visceral pain

Idiopathic
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 inammation of the central nervous system (glial activation)

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Outline
1. Opioids have analgesic and hedonic properties 2. Opioids are good pain relievers because of their combined analgesic and hedonic properties 3. Opioids are less effective in chronic pain states, due in part to changes in the hedonic system 4. In chronic pain, the motivation to take opioids is partly driven by analgesia 5. Opioid dependent states parallel the chronic pain state

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Definitions

Hedonic: Relating to the pleasurable affect of opioids Analgesia: relating to the pain relieving attributes of opioids

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1. Opioids have analgesic and hedonic properties

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Hedonic mechanisms of opioids

The ventral tegmental area (VTA) is a brain

nuclei within the mesolimbic system (meso=mid brain, limbic=striatum) that contains dopaminergic cell bodies. Opioids act here to increase dopamine release by inhibiting the inhibition of GABAergic interneurons acting on dopaminergic neurons (Disinhibition)

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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 regions involved 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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Lesion of the mesolimbic dopamine system reduces opioid _l_ 70 analgesia

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Injection of low dose of formalin into the hind paw of the mouse results in a localized inflammatory state that is accompanied by a persistent pain sensation. The level of analgesia can be measured by testing paw withdrawal thresholds of thermal or mechanical stimuli (graphed here as a percentage). Specific lesions of the VTA significantly reduced morphine analgesia.

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FIG. 2. The analgesic effect of amphetamine and morphine in rats with 6-hydroxydopamine-induced lesions of the ventral tegmental dopamine cells or with sham lesions (0.05% ascorbic acid vehicle). In sham-lesioned rats both morphine and amphetamine produced significant (.0<0.05)

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-communicating animals

Self-administration

Animals are implanted with an intravenous catheter (usually) connected to a reservoir of drug. Animals are 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 press the 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 Ratio 3, FR3) to receive one drug infusion rather than just once (FR1).
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How to measure reward in non-communicating animals

Conditioned place preference

Drug

Saline

Post conditioning Day

A 2 (or sometimes 3) chambered apparatus is used. The two chambers are distinguished from one another 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 days for 20-30 minutes, and receive either drug or saline injection. Over time, the animal learns to associate the drug sensation with a specific chamber. On the final post conditioning day, animals are placed in the apparatus, and the door connecting the two chambers is opened, allowing the animal access to both chambers. 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.
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The reward system is disrupted in chronic pain

Opioid self administration is reduced in chronic pain animals, when compared to sham (non pain) controls. Only high doses of opioids which are analgesic, are self administered at normal levels

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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 a semi-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 nucleus accumbens 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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Relief of pain decreases opioid self administration

If you relieve the pain with a nonrewarding analgesic drug (clonidine), opioid self-administration is decreased in chronic pain states. Clonidine has no effect in shams (non-pain controls) on opioid self administration

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Relief of pain induces conditioned place preference

8 conditioning sessions

2 conditioning sessions

If you relieve the pain with a non-rewarding analgesic drug (lidocaine directly on the injured peripheral nerve or intrathecal clonidine) you can block opioid place preference as well in chronic pain (SNL=spinal nerve ligation) but not sham controls

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5. Opioid dependent states parallel chronic pain states

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Cycle of opioid addiction

Addicts seek opioids to relieve the 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
- high levels of circulating endogenous opioids

Opioid dependence
- chronic opiate exposure

- lowered analgesic efcacy

- tolerance

- glial activation/inammation

- glial activation/inammation

- lowered dopamine release in the striatum in - lowered dopamine release in the striatum in response to opioids response 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 glial activation (inflammation) throughout the brain. This glial activation directly affects excitability of surrounding neurons, and contributes to the neurological adaptation associated with pathology

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Parallels between opioid dependence and chronic pain

Chronic pain
- high levels of circulating endogenous opioids

Opioid dependence
- chronic opiate exposure

- lowered analgesic efcacy

- tolerance

- glial activation/inammation

- glial activation/inammation

- lowered dopamine release in the striatum in - lowered dopamine release in the striatum in response to opioids response to opioids

- seek opioids to relieve pain

- seek opioids to relieve withdrawal

Thursday, February 14, 13

Questions?

Anna Taylor, PhD Hatos Center for Neuropharmacology

ataylor1@ucla.edu (310)206-7883
Thursday, February 14, 13