Pharmacology of pain Flashcards
1
Q
LO
A
- The endogenous pharmacology of the pain pathways:
Chemical transmitters – signal a noxious stimulus
Receptor subtypes – detect/respond to transmitters
Signalling mechanisms – conduction and transmission
Periphery & spinal cord
- How drugs that alleviate pain exert their actions:
Transmitters
Receptors
Signalling mechanisms
- The management of pain using different pharmacological agents:
Capsaicin, Ketamine (structure, mode of action (MoA))
Opioid analgesics (eg: morphine – structure, MoA)
2
Q
Lecture content
A
- Introduction to pain: neuronal pathways that transmit noxious stimuli (BIOL2014)
- Endogenous pharmacology of the pain pathways
- How different chemicals stimulate peripheral nociceptive fibres and modulate pain pathways: activation of nociceptors by noxious substances, ‘pain channels – VR1/TRPV1’; neurotransmitters and receptors involved
- Analgesics: overview and focus on morphine as an analgesic (Where, how, cellular activity and circuitry function)
3
Q
Pain is a physiological protection mechanism, explain some examples of how we respond to harmful stimuli and adapt our behaviour
A
- Withdrawal response – prevent continued tissue damage e.g touching something hot to stop getting burnt
- Immobilization (if pain is so severe)– helps to facilitate wound healing e.g., breaking ankle
- Affective responses – future behaviours (emotional responses, information stored to modify future behaviours)
4
Q
Tell me about acute response and chronic (prolonged, presistent)
A
- Amputees – phantom limb pain (years)
- Arthritis – joint pain (cannot be cured)
- Cancer – tumour physical or chemical
5
Q
What is neuropathic pain?
A
- chronic pain
- nerve damage (CNS or periphery)
- no longer protective (originates from within the nervous system)
6
Q
Give some examples of neuropathic pain?
A
- Herpes zooster – viral infection (post herpetic neuralgia)
- Diabetes – metabolic (diabetic neuropathy)
- Multiple sclerosis – immune response
7
Q
What can continues pain lead to?
A
Long-term illness if not treated
8
Q
Whats the clinical problem with neuropathic pain?
A
Need for analgestics
9
Q
Give two examples for analgesics?
A
NSAIDs (non-steroidal anti-inflammatory drugs) and Opioids (morphine-like analgesics)
10
Q
Give some other examples of analgesics and what they are prescribed for
A
1) cannabis for MS (Cannabidiol (Phytocannabinoid) – acts on endogenous endocannabinoid system. Treatment for neuropathic and cancer pain; not leagal in all countries)
2) antidepressants can be co-prescribed for chronic pain (Ones emotional state can have an effect on their perception of pain i.e., feel bad then experience more pain)
11
Q
What two componenets can pain be divided into?
A
Nociception and pain
12
Q
Whats Nociception?
A
Nociception: the physiological process of detection of a noxious stimulus and tissue damage
13
Q
Whats pain?
A
Pain: the effect of the noxious stimuli behaviour; a consequence of higher order processing in the brain, a very subjective phenomenon (Affective Component)
14
Q
Sensory information from the periphery can be sent back to the CNS via a number of different fibre type. What are these fibre types?
A
- Aalpha and Abeta fibres
- Adelta fibres
- C fibre
15
Q
Tell me about Aalpha and Abeta fibres
A
16
Q
Tell me about Adelta fibres
A
17
Q
Tell me about C fibres
A
18
Q
What primary afferent axons are activated when tissue damage starts to occur?
A
19
Q
What is the ‘pain’ pathway?
A
Spinothalamic tract –>
discriminative/recognition/where/type (neospinothalamic) Spinoreticulothalamic tract –>
(limbic) affective-motivational aspect (paleospinothalamic)
20
Q
Where does the regulation of pain transmission occur?
A
dorsal horn
21
Q
Descending pathway
A
22
Q
Afferent inhibition (gate theory)
A
23
Q
example
A
24
Q
Whats Hyperalgesia?
A
25
Overview of modulatory mechanisms
26
Tell me about peripheral sensitisation
Why is it called this
27
What is substance P?
**SP =** A neuropeptide, belong to Tachykinin family. Preprotachykinin
28
Whats CGRP?
CGRP= A neuropeptide (37AA). Calcitonin family
29
Explain peripheral sensitisation and the involvement of substance P and CGRP
30
Tell me about the NGF (nerve growth factor) and peripheral sensitisation
31
Whats NGF?
NGF = part of the neurotrophin family, axonal growth during development & nociception pathway
32
Descending pathway
33
Tell me the different sites of opioids action and the effect they have there
34
What we considered in the following slides...
* The channels and receptors underlying the chemical response following a noxious stimuli/tissue damage
* In the context of a C-fibre nociceptor
* How changes in C-fibre terminal activity are brought about (signalling mechanisms that bring about peripheral sensitization)
* Chemicals released upon tissue damage can act
directly to activate nociceptors
indirectly to sensitize nociceptors
35
Why are nociceptors described as being polymodal?
36
Tell me about the chemicals that activate nociceptors
37
Compare direct vs indirect sensitisation
38
Explain about phosphorylation of VR1 and VGSC and what it can lead to
39
Explain about the effects of Bradykinin and sensitivity
40
Tell me about the effects of prostaglandins and sensitivity
41
Cross talk between PG and BK pathways to sensitise noiceptors
42
Tell me about the effect of opiate and cation channels on sensitivity?
43
Tell me about the chemical that activate nociceptors
44
**Summary**
* **Pain pathways: nociceptors, spinothalamic, spinoreticulothalamic**
* **Tissue injury can cause the release of several chemical mediators from the tissue (eg prostaglandins, bradykinin, NGF) and the C-fibre nociceptor nerve terminals (Substance P and CGRP) to cause a peripheral sensitization**
* **C-fibre nociceptors are polymodal and express both ionotropic and metabotropic receptors that can respond to the chemicals being released by the damaged tissue**
* **Intracellular signalling cascades allow cross talk between metabotropic and ionotropic receptor types and voltage gated sodium channels to cause a sensitization of the C-fibre nociceptor**
45
Tell me the 'pain pathway' and transmitters and how there is a link between the periphery and the CNS?
46
What is the pain channel receptor and what is it described as being?
VR1 (Vanilloid Receptor 1) = Capsaicin Receptor = **TRPV1**
TRPV1 is described as being **polymodal**
47
What are the reasons what TRPV1 is considered polymodal?
* Porotons
* Capsaicin
* Anandamide
* Noxious stimuli
Heat
48
What two compounds can activate the VR1 receptor?
Bradykinin and NGF
49
What can stimulate the Nav?
Prostaglandins
50
What stimulates the potassium channel?
Opiates and Anandamide
51
The pain channel overview
52
What family is **Capsaicin** a part of?
Vanilloid family
53
Tell me the structure of Capsaicin and some properties
54
What is the compound that gives chillies their hotness?
Capsaicin
55
Capsaicin- like molecules
56
Tell me about the compound **Resiniferatoxin**
57
What fibres can Capsaicin activate and what does this result in?
Can activate **C fibres** (smaller diameter, unmyelinated, slower conductance)
This elicits **sensation of heat and pain**
58
What are C fibres?
Where are they found?
Role?
C fibers are one class of nerve fiber found in the nerves of the somatic sensory system.
They are afferent fibers, conveying input signals from the periphery to the central nervous system.
59
What does a challenge with capsaicin lead to?
a challenge with capsaicin leads to a reduction or loss of responsiveness of the nociceptor to noxious inputs
60
Why is there a hunt for the capsaicin receptor?
* endogenous ‘pain channel?’
* Analgesic properties
And its treatment for pain
61
62
Cellular response maps to the 'hotness of pepper'
What is the rating scale called?
63
What type of channel is the receptor for Capsaicin?
64
Tell me about the structrue of TRP channel receptors?
* Composed of 6 membrane-spanning helices (S1-S6) with intracellular N- and C-termini
* **Intracelluarly:**
- Temperature sensor (Chimera's)
- Phosphorylation and dephosphorylation
- Ankyrin repeats
- **Capsaicin binding**
* **Extracelluarly:**
****-Pore-forming region
- Proton sensor
- C
65
Noxious heat stimuli decrease in response to what?
VR1 KO
66
What does VR1 KO have decreased thermal hypersensitivity in ?
Neurogenic inflammation
67
What is the TRPV1 receptor important for?
68
Tell me what processes which occur with TRPV and sensitisation to thermal stimuli?
* Activation of the TRPV (capsaicin receptor) causes local release of substance P and CGRP which leads to intense responses in the local vasculature, increased permeability and vasodilation
* In addition, a reduction in the temperature threshold for TRPV activation can further contribute to thermal hypersensitivity and pain following tissue injury and inflammation
69
What are the activators of TRP1?
* Capsaicin
* Endogenous agonists
* Acidosis (H+)
* Heat (\>40˚c)
* Na+
* Ca2+
70
Tell me the effects of increased Ca2+ to the TRPV1 receptor?
* Sodium and calcium. Activation of TRP channel leads to the influx of the cations. Influx in ratio of 1Na+: 8Ca2+
* Increase calcium leads to increase toxicity to the cell which can impair the normal function of the nociceptor
71
Capsaicin given to neonatal mice causes a loss of what?
nociceptors
72
Capsaicin cream is used for the treatment of what?
Tell me why its used?
Some side effects?
Problems with this form of capsaicin?
Neuralgia
* Capsaicin not only **causes pain**, but also **exhibits analgesic properties**, particularly when used to treat neuropathic pain (chronic pain)
* **Burning sensation on initial application**
* Requires frequent and repeat applications = **poor patient compliance** (therefore other methods for administering capsaicin had to be made)
73
What were capsaicin patches used for?
Capsaicin patches used for the treatment of post-herpetic neuralgia
74
What does the inactivation of VG Ca2+ channels lead to?
Inhibition of peptide release Substance P and CGRP
75
The mechanisms underlying the analgesic effects of capsaicin?
76
Tell me about the mechanisms underlying the analgesic effects of capsaicin cream
* **Lipophilic** = v.good topical peripheral analgesic
* **Resides at the target site**
* **Not absorbed across the skin** into the blood stream
* **Cannot enter** the **systemic blood flow**
* **Minimises non-specific effects**
77
What are the 2 key excitatory neurotransmitters?
What fibres releases them?
**Glutamat**e (A-delta and C-fibres)
**Substance P** (C-fibres)
78
What receptor does Substance P signals via?
GPCR known as **NK-1**
79
What are the two forms of GPCR?
**Ionotropic** (membrane-bound ligand gated ion channels) and **metabotropic** (membrane bound and activated via indirect metabotropic process)
80
What are the ion channels associated with ionotropic receptors?
Tell me about them and what problems they are associated with?
1. **AMPA**
2. **Kainate**
3. **NMDA**
* Diverse and wide-ranging role
* Autism/Schizophrenia/Pain
81
Where is NK-1 expressed?
PNS and CNS
82
What are the receptors associated with noxious transmission in the dorsal horn?
What type of receptor are they?
Their ligand?
Mg2+ ion?
Action?
Function?
Speed of inactivation?
83
What is the NMDA receptor activated upon?
Whats required for activation?
What happens once activated?
* NMDA activation is dependent upon **glutamate/glycine binding** to their respective sites AND **depolarization of the neuron to remove the magnesium block**
* The **two events must occur together** for the receptor to be activated
* Once activated this leads to an **influx of calcium ions = depolarization**
84
What is meant by "WIND-UP"?
85
In order to demonstrate windup electrophysiological recordings were made from an animal model...
86
Pharmacological analysis demonstrates that what receptors are required for wind-up?
87
Pharmacological analysis supports that what receptors underpin increased sense of pain?
88
Tell me about NMDA and substance P antagonists as analgesics
89
**LO**
90
Tell me two effects of opioids?
* Increase analgesics
* Decrease dependence
91
**Summary of Lecture II**
92
Tell me the analgesic effects of opioids
93
Tell me the analgesic ladder for the clinical administration of opioids to control pain?
94
What is an opioid?
'any substance natural, endogenous or synthetic that produces morphine-like effects blocked by naloxone ‘
95
What are the 3 types of opioids?
1. Endogenous opioid
2. Antagonist opioid
3. Opioid analgesic
96
Give some examples of endogenous opioids?
* Endorphins
* Dynorphins
* Enkephalins
* (Limbic system and Spinal cord)
97
Give some examples of analgesic opioids?
* Nalorphine
* Naloxone
* Naltrexone
98
Give some examples of analgesic opioids?
* Morphine
* Codeine
* Diamorphine
* Methadone series
* Phenylpiperidine series
* Benzomorphan series
99
Tell me about morphines link to opium?
* Opium = resin from the poppy flower --\> 20 alkaloids
* Morphine --\> 10% of the total alkaloids
100
What does morphine effect?
CNS and GI tract
101
What components does morphine have?
Antinociceptive & Affective component
102
Tell me some effects of taking morphine?
* Mood altering – euphoria, well being
* Respiratory depression (increased arterial PCO2)
* Sleep (insomnia)
* Nausea and Vomiting
* Pupillary constriction (oculomotor centre)
* GI tract --\> increased motility, constipation
* Highly addictive
* Tolerance
* Physical and Psychological dependence
103
Morphine structure
Has Phenanthrene in its structure
104
What is the most commercial opioid?
Codeine
105
What is codeine metabolised to?
Morphine
106
What is codeine used of for?
Why is this used instead of morphine?
* Pain killer with very little or no euphoria
* Limits the abuse potential (vs morphine)
107
Whats the drug used for sleep and GI motility?
What are its components?
**Solpadol** (30mg codeine & 500mg paracetamol) – sleep and gi motility
108
What % of analgesic potency does codeine have compared to morphine?
20%
109
What type of pain is codeine used for?
Mild pain (eg. backaches)
110
What is the structure of codeine?
Morphine has hydroxyl group whilst codeine has methyl group
111
Tell me how Heroin/ diamorphine is taken?
Tell me some properties of heroin?
What is it metabolised into?
What is it classified as?
* **Injected** directly into blood stream
* Very **lipid soluble** (can cross BBB)
* **Highly potent**
* **short lasting**
* **Metabolised to morphine**
* Classified as a **Class A drug**
112
Structure of heroin?
113
What is Naloxone?
**Opioid antagonists** (acts on all receptor subtypes)
114
Can Naloxone act on its own?
Little effect on its own
115
What is naloxone used for?
* Opioid poisoning (O.D.)
* Respiratory depression (new borns)
116
How is Naloxone administered and how long does it act for?
* Intravenously
* Short acting 2-4 hours
117
Structure of Naloxone
118
What is Naltrexone?
Lasts for?
Used for?
structure...
* **Opioid antagonist** (acts on all receptor subtypes)
* **Longer acting** (\>2-4 hours ~ 10hrs)
* used for **Alcohol dependence**
119
Name two compounds in the Phenylpiperidine series?
Pethidine and Fentanyl
120
Are the compounds Pethidine and fentanyl natural?
They are fully synthetic
121
What are Pethidine & Fentanyl in the Phenylpiperidine series used for?
Tell me their potency and duration?
* Less potent and Shorter duration
* Labour and Post-operative pain
122
Phenylpiperidine series structure
123
What has a longer duration of action; methadone series or morphine?
Longer duration of action (24-36 hrs) vs morphine (4-6 hrs)
124
What is the methadone series used for?
How does it work?
* Opioid substitution therapy in heroin addiction
* effects are less intense = decreases physical dependence
* Less euphoria than heroin and morphine
* Blocks the effects of heroin and morphine (euphoria)
125
Methadone series structure
126
Give an example of a compound in the Benzomorphan series?
Pentazocine
127
Tell me about Pentazocine i.e. uses, properties etc.
Structure...
* Synthetic Opioid
* Mixed agonist-antagonist (depends on receptor subtype)
* Used as an analgesic – can cause dysphoria
128
The molecular properties can determine analgesic properties. This is seen in steroisomers, give an example and tell me about their different properties
* **Synthetic opioids**
* **Levorphan**- 8x more potent, highly addictive and same side effects
* **Dextrophan** – no analgesic properties and is non-addictive
129
Tell me some pharmacological actions of opioid analgesics
* analgesia
* sedation
* respiratory depression
* pupillary constriction
* bradycardia
* euphoria
* dysphoria
* reduced gastrointestinal motility
* dependence
* tolerance
* withdrawal syndrome
note, that some of these actions are clinically useful- others will limit the clinical use.
130
In 1973, what did Pert and Synder report about naloxone?
1973: Pert and Snyder reported high affinity naloxone binding sites in mammalian brain
i. e., there are specific OPIOID RECEPTORS in brain
131
What family to opioid receptors belong to?
Opioid receptors belong to the G protein-coupled receptor family of receptors
132
Different opioid receptor agonists do not all exert the same range of effects
not all opioids can relieve withdrawal effects in morphine-dependent animals
receptor subtypes have been cloned and sequenced from mammalian brain
Name some ifferent receptor subtypes?
* MU ( µ) RECEPTORS
* DELTA RECEPTORS
* KAPPA RECEPTORS
* SIGMA RECEPTORS
133
Tell me about the µ opioid receptor subtype
* RESPONSIBLE FOR ANALGESIC ACTIONS OF MORPHINE
* ALSO, RESPIRATORY DEPRESSION, EUPHORIA, SEDATION AND DEPENDENCE
134
Tell me the delta opioid receptor subtype
PROBABLY MORE IMPORTANT IN PERIPHERY, BUT ALSO MAY CONTRIBUTE TO ANALGESIA
135
Tell me about kappa opioid receptor subtypes
CONTRIBUTE TO ANALGESIA; MAY ELICIT SEDATION AND DYSPHORIA; DO NOT CONTRIBUTE TO DEPENDENCE; SOME ANALGESICS ARE KAPPA SELECTIVE
136
Tell me about sigma opioid receptor subtypes
* NOT TRUE OPIOID RECEPTOR; Accounts for psychotomimetic effects of some opioids (anxiety, hallucinations, dysphoria)
* Only certain opioids bind, eg: PENTAZOCINE (BENZOMORPHANS)
* Can bind a number of other psychotropic drugs
137
Nociceptive pathway
138
The different role of the opioid receptor subtypes
139
Tell me about the cellular actions of the opioids
140
The opioid receptor subtypes selectivity of opioid analgesics
141
Tell me the two effects of opioids on the nociceptive pathways
1. Peripheral actions
2. In the spinal cord
142
Tell me the effects of opioids on the nociceptive pathways in the periphery
PERIPHERAL ACTIONS
* inhibit discharge of nociceptive afferents
* morphine also releases histamine from mast cells
143
Tell me the effects of opioids on the nociceptive pathways in the spinal cord
144
What does morphine inhibit the release of in the dorsal horn?
The release of SubP
145
What is PAG?
Midbrain periaqueductal gray (PAG) inhibits nociceptive inputs to sacral dorsal horn nociceptive neurons through alpha2-adrenergic receptors.
146
Tell me about supraspinal effects (inj. PAG)
* relevant to the affective component of pain
* (the alteration of behaviour and mood).
* N.B. Euphoric effects vary according to the opioid;
* Codeine causes little euphoria
147
Tell me the systems behind: euphoria, respiratory depression, nausea and vomiting
* **Euphoria** – limbic system (mesolimbic – reward circuit)
* **Respiratory depression** – decreases CO2 chemosensitivity of respiratory centre in medulla
* **Nausea and vomiting** – medulla (chemoreceptor trigger zone) – anti-emetic co-prescribed
148
What are the supraspinal effects all mediated through?
All these are mediated through the inhibitory actions of opioids in the relevant CNS centres.
## Footnote
*note that respiratory depression is one of the major effects limiting the clinical use of the opioids and is the commonest cause of death in acute opioid poisoning.*
149
What can a repetitive administration of morphine lead to?
With repetitive administration of morphine an increase in dose is required to give the same level of analgesia. This can lead to tolerance.
150
Experimental demonstration of tolerance
151
Development of morphone tolerance in mice
152
Changes in the cellular processes that mediate the effects of morphine
What is morphone tolerance caused by?
153
What are the features of tolerance?
* tolerance develops rapidly (12-24hrs)
* cross-tolerance occurs between agonists acting at the same receptors
* tolerance is reversible
* Adaptive up-regulation of adenylyl cyclase
* tolerance is not due to increased metabolism of opioids or opioid receptor downregulation
154
What are the two types of dependence?
* physical dependence (withdrawl response)
* Psychological dependence
155
What is psychological dependence?
* The first of these is responsible for the withdrawal syndrome colloquially called 'cold turkey'.
* The second is responsible for drug craving and addiction
156
What are symptoms of physical dependence?
Chronic morphine followed by removal (or naloxone/ naltrexone administration) gives symptoms resembling flu:
* diarrhoea
* nausea
* sweating
* pupillary dilation
* piloerection
* Fever
* Irritability
* Weight loss
* These symptoms may persist for up to 10 days
157
What are the symptoms of psychological dependence?
* **Drug craving and drug** seeking which involves the brain **'reward pathway’**
* Symptoms last longer than those of physical dependence (months/years)
* Major cause of relapse but rare in patients administered opioids as analgesics
* Methadone is often used in replacement therapy:
* Causes less euphoria – used in controlled withdrawal in people with opioid dependence
* Slow onset of action and long half-life = withdrawal symptoms are more gradual and less intense than with morphine or heroin
158
**Summary**
* **What neurochemical processes contribute to pain? (L1)**
* **TRPV1 channels on nociceptors – can be targeted by capsaicin to provide pain relief (L2)**
* **Glutamate and substance P as neurotransmitters in the pain pathways and wind-up (L2)**
* **How do opioids exert their actions? (L3)**
* **Morphine and opioid analgesics/ inhibitory actions on neurotransmission in pain pathways mediated via an interaction with specific opioid receptors**
