Opioid Tolerance and Dependence Flashcards
What is tolerance?
The need to increase a dose to maintain a given effect
Develops rapidly and compromises therapy with increasing risk of side effects
What is dependence?
Consists of physical dependence - the development of withdrawal symptoms
A strong pyschological dependence- cravings / desire to take the drug despite an obvious adverse consequence
What is the main problem with tolerance?
Side effects are much less subject to tolerance and so we cannot just keep increasing the dose
Side effects include ; emesis (vomiting), euphoria, respiratory depression, constipation and pupil constriction
What is cross-tolerance?
Where one drug causes tolerance to a different drug
Common with opioid but not normally complete
Important for opioids to be rotated so that tolerance doesn’t develop
How can tolerance develop in general?
At the level of receptor signalling, repeated agonist stimulation could cause desensitisation (loss of opioid function) by;
- reduction in agonist affinity
- uncoupling from Gi/o proteins ~(reduced downstream signalling)
- receptor internalisation and down regulation
How can opioid receptors become desensitised?
Agonist affinity - long term exposure to some agonists can desensitise ORs with regard to post receptor signalling (not in opioids)
What relationship is shown between opioid agonist and affinity and tolerance?
Counterintuitive
- lower efficacy agonists develop / cause more tolerance than higher efficacy agents
- maybe because high efficacy agonists have more receptor reserve and so dont have to occupy all available receptors to produce full response
How does internalization cause tolerance to opioids?
- μ-opioid receptor internalisation rapidly follows agonist activation
-receptor phosphorylation and recruitment of beta-arrestn protein that pulls into the cell
No.2 is agonist dependent (endogenous peptide ligands, etorphine and dihydroetorphine higher)
Morphine fails to cause much internalisation
How can tolerance develop by disrupting a pathway?
- uncoupling of the receptor from the downstream signalling pathway
- phosphorylation by several different protein kinases
How does downregulation cause opioid tolerance?
- μ-opioid receptor down regulation after prolonged exposure the disappearance of receptors from cell locations by proteolysis, lysosomes/proteasomes
No.3 also agonist selective, higher with high efficacy agonists (etorphine)
Limited effect of morphine on receptor numbers
What is the best supported theory of opioid tolerance?
Alterations in signalling mechanisms
4. Upregulation of the expression of adenylyl cyclase in many areas of the CNS
-increases capacity for cAMP generation
-reduced sensitivity to inhibition via Galphai
Opioid receptors can couple with both Gi and Gs proteins; the stimulatory and inhibitory effects mediated have been demonstrated for most opioids therefore is their a switch in signalling?
What is opioid induced hyperalgesia?
Increased pain sensitivity
Describe how opioid induced hyperalgesia develops
Sensitisation of pro-nociceptive mechanisms on chronic opioid treatment
Shifting balance towards Gs excitatory pathway
What is a factor that affects our opioid response (especially to tolerance)?
Age dependent difference
Analgesic potency of morphine increases exponentially in rats from 3-14 days old
Parallel increase in post natal development of μ opioid receptors to Gi
Future treatments to avoid tolerance to opioids?
Growing evidence of glutamate role in tolerance development
