Pain physiology and analgesic therapies Flashcards
What is pain?
International association for the study of pain (IASP): Pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.
- A personal experience that is influenced to varying degrees by biological, psychological, and social factors.
- Pain and nociception are different phenomena.
- Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being.
A first characterization of pain types…
ACUTE pain can be intense and is mostly short-lived. In
most cases it indicates tissue damage and/or an injury.
CHRONIC pain last much longer compared to acute pain. Mild and severe forms are known.
Classification of pain (according to involved structures)
Nociceptive pain (acute pain) is caused by stimulation of nociceptors, a set of specialized peripheral nerve cells.
-> SOMATIC pain is associated with the skin, skeletal muscles, bones, joints, fibers.
Stimuli: chemicals, temperature, mechanical stress.
-> VISCERAL pain develops in the thorax (chest, abdomen, back…).
Stimuli: insufficient blood supply, inflammation.
-> NEUROPATHIC pain (nerve pain) is known as pinched or trapped nerve pain.
Causes: nerve degeneration (e.g. stroke, multiple sclerosis, insufficient blood supply, specific gene mutations), nerve infection, acute pain may turn into neuropathic pain
-> SYMPATHETIC pain involves damage of sympathetic nerves which control blood supply and sweating of the skin.
Causes: Soft tissue injuries.
Other forms of pain are phantom pain (amputation), psychogenic pain (mental and emotional factors e.g. hypochondriasis) or breakthrough pain (e.g. in cancer).
Pain-related peripheral structures
-> NOCIRECEPTORS are primary sensory neurons, which are activated by stimuli capable of causing tissue damage. Characteristic thresholds or sensitivities distinguish them from other sensory nerve fibers.
-> Nociceptive nerve endings are not myelinated; they contain TRANSDUCTION PROTEINS that translate noxious stimuli into electrical signals.
DRG (dorsal root ganglia)
- pseudo unipolar neurons
- pain signaling
- fast (5-50 m/s) Ad fibers and slow (1 m/s) C fibers (first and second pain phenomenon)
- thin layer, non myelinated axons respond to noxious stimuli
- contains interneurons respond to noxious, non noxious stimuli (modulation of sensory input)
- interneurons respond to signals from Beta fibers
- thickest layer respond to non noxious input
- contact to layer II respond to signals form Abeta, Agamma, C fibers
-> different kinds of nociceptors detect different kind of pains
Hyperalgesia
-> Increased sensitivity to noxious stimuli (sensitization of nociceptors; amplification of the signal) as the consequence of tissue damage (e.g. after stroke), irritants (e.g. in the periphery), inflammation
* Inflammatory or allergic response
* Dysregulation in the brain and/or nociceptors
* Involves immune cells
* Severe forms
-> Treatment with e.g. Gabapentin, NMDA antagonists (e.g. Dextromethorphan, also opioids like Methadone and others)
-> side effects: learning/memory deficits, psychosis, ataxia.
Allodynia
-> Non-noxious signals cause pain by indirect activation of nociceptors
-> Fast adapting Ab fibers gain access to nociceptors and activate them (hypothesis: neurochemistry of GABA changes at the gate from inhibitory to excitatory)
* Causes: nerve damage, injury in the spinal cord
* Mechanosensitive and nociceptive fibers may contact the same interneurons in the dorsal horn -> wrong input causes pain (e.g. sunburn)
-> Treatment depends on type: opioids, NaV channel blockers (LA)
Peripheral pain signaling depends on ion channels
- PERIPHERAL TERMINAL
Transduction of noxious stimuli into an electrical signal
Specialized transducer proteins recognize heat / cold, chemicals or mechanical stimuli. - DORSAL ROOT GANGLION
Propagation of the signal
Voltage-gated ion channels generate action potentials and support their propagation along the axon. - SPINAL CORD
Synaptic transmission
Transmitter-activated ion channels.
-> Nav 1.8 and and Nav 1.9 are also implicated in human pain perception
Transduction channelopathies observed in mice
TRPs: TRPV1, TRPV4, TRPM 8, TRPA1
ASICs: ASIC 1, ASIC2, ASIC3
P2XRs: P2X3, P2X4, P2X7
Ion channels involved in transduction
- TRP: Transient Receptor Potential
- TRPV1 senses moderate heat threshold 43 °C
- TRPV2 senses noxious heat > 50 °C
- Non-selective cation channel
- C fibers and type-II Ad fibers
- ASIC: Acid-Sensing Ion Channel
- Widely expressed in the CNS and the PNS
- ASIC1a/b, ASIC2a/b and ASIC3 are proton gated (pH0.5 5;
suggestive of Glutamate or Aspartate dependence), ASIC4 not - Touch sensation, inflammatory processes
- P2X: Purinoreceptor
- Seven members: P2X1-7 , 500-600 aa, gated by extracellular ATP
- Homo- and heteromers
- Active in damaged and inflamed tissue (50 μM – 5 mM ATP)
- Expressed in C fibers
Inflammation causes pain
Inflammatory mediators (IMs) released from cells during tissue injury sensitize nociceptors
* Bradykinin, H+, 5HT, ATP, Neurotrophins (nerve growth factors), Leukotrienes, Prostaglandins (PGE2, PGI2) are the most important IMs
* Some IMs interfere directly with ion channels; others use different pathways to sensitize nociceptors
Fever is part of the inflammatory response
* Tissue damage, inflammation, transplant rejection or malignancy enhance the levels of Cytokines (e.g. IL-1β, IL-6, TNF-α) and Interferons which act as endogenous pyrogens
* PGE2 is one of the main triggers of fever; it can cross the blood-brain-barrier and stimulate EP3 (and possibly also EP1) receptors that are exposed on neurons involved in temperature regulation
Transduction phenotypes are treated with COX inhibitors
Receptors IP, DP1, EP2 and EP4: via Gs-mediated increase in cAMP
Receptors EP1, FP and TP: via Gq-mediated increase in Ca2+
Receptor EP3 via Gi-mediated decrease of cAMP
Transduction phenotypes are treated with COX inhibitors
-> Acetylsalicyclic acid (ASA, Aspirin)
Acetylsalicylic acid (ASA, Aspirin)
* T1/2 = 20 min
* Rapidly deacetylated to salicyclic acid (SA) which has a T1/2 of 2-3 h
* Protein binding: 50 – 70% for ASA and 70 – 98% for SA
* Acts via COX-1/2 inhibition
* Permanent platelet inhibition (COX-1)
* Clotting time increases
Transduction phenotypes are treated with COX inhibitors
-> Dicophenac
Diclophenac (acetic acid derivative)
* T1/2=1.2–2h
* Protein binding: 99%
* Acts via COX-1/2 inhibition
* First-pass effect
* Oral availability 50%
* More potent as ASA
Transduction phenotypes are treated with COX inhibitors
-> Ibuprofen (propionic acid derivative)
Ibuprofen (propionic acid derivative)
* T1/2=2–4h
* Protein binding: 99%
* Acts via COX-1/2 inhibition
* As potent as ASA
Transduction phenotypes are treated with COX inhibitors
-> Paracetamol (para-aminophenol derivative)
Paracetamol (para-aminophenol derivative)
Not a classical NSAID, i.e. no anti-inflammatory activity !
* T1/2 = 2 h
* Protein binding: 20 – 50%
* Seems to prefer COX-2 over COX-1
* Almost no effect on platelet aggregation
* As potent as ASA in terms of analgesic activity
Pain as a channel-patchy: Transmission
-> Pain channelopathies observed in mice
NaVs
Nav 1.3
Nav 1.7 -> PNS, pain relevant
Nav 1.8 -> DRG, pain-relevant
Nav 1.9 -> DRG, PNS, pain-relevant
- NaV1.7/1.8 channels initiate action potentials
- NaV1.9 channels modulate the resting membrane potential
Ion channels involved in Transmission
-> voltage independent
- SK: Small Conductance
- 4 members SK1-4 (KCa2.1-2.4)
- Voltage independent, K+ selective
- Strongly Ca2+ dependent, binds CaM,CK2, PP2A
- ir: inward rectifying
- No intrinsic voltage sensor, K+ selective
- Inward rectification via endogenous polyamines (spermidine) or Mg2+
- Some of them: gating via intracellular proteins (G-proteins)
- Pain relevant: GIRK (Kir3 family)
Nav1.7 related channelopathies
CIP Congenital Indifference to Pain (NaV1.7)
* Rare disorder
* Both gene copies must be affected
IEM Inherited (Primary) Erythermalgia (NaV1.7) (also: Erythromelalgia)
* Severe burning pain in the extremities, swelling
* Blocked blood vessels, red skin, inflammation
* Attacks are triggered by heat, pressure, alcohol, caffeine and last hours
* First channelopathy associated with a chronic pain phenotype in human (2004)
PEPD Paroxysmal Extreme Pain Disorder (NaV1.7)
* Flushing and pain in mandibular, ocular and rectal regions
SFN Small Fiber Neuropathy (NaV1.7 and NaV1.8)
* Unpleasant sensation e.g. feeling of “pins and needles”
* Damage of C fibers
Mechanism of known NaV1.7 channelopathies
IEM -> sub-threshold activation, impaired inactivation
PEPD -> impaired inactivation, increased availability of channels
SFN -> increased resurgent current
Local anesthetics inhibit NaV channels
Treatment of pain and arrhythmias with local anesthetics (LA) e.g.: Cocaine, Procaine, Lidocaine, Bupivacaine, Robivacine (long-lasting activity)
LAs have a pKa 8 -> only 3-20 % are lipid soluble (ionization, especially in inflamed tissue)
Anticonvulsants inhibit NaV channels
Anticonvulsants can be useful for the treatment of select NaV channel malfunctions associated with pain phenotypes:
Carbamazepine is used to treat epilepsy and neuropathic pain.
Stabilizes the fast-inactivated state of the channels.
Success of Carbamazepine depends on the specific NaV malfunction.
PEPD patients respond generally well to Carbamazepine.
Adverse effects: nausea, drowsiness, vomiting…
Lacosamide is an anticonvulsant with only minor or no analgesic activity.
Stabilizes the “slow” inactivated state of the channels.
A NaV1.9 channelopathy causing indifference to pain
- Two patients with lack of pain perception carry the same de novo mutation in one copy of SCN11A (NaV1.9-L811P)
- Overlapping symptoms:
- Inability to experience pain
- Self-mutilating behavior
- Slow healing wounds
- Painless fractures
- Muscular weakness
- Extreme sweating
- Gastrointestinal dysfunction (parenteral nutrition)
Single APs (knock-in animals) -> shorter action potentials and a depolarized resting potential in heterozygous DRGs
A NaV1.9 channelopathy cuasing indifference to pain
-> mEPSCs (Miniature Excitatory Postsynaptic Currents) from knock-in animals
Hyperactive NaV1.9 channels increases the RMP, this inactivates other ion channels, reduces intracellular Ca2+ and transmitter release.
Pain channelopathies observed in mice -> Synaptic signal transmission
CaV2.1 Increased mechanical threshold in inflammatory and neuropathic pain
CaV2.2 suppressed responses to inflammatory pain. Reduced symptoms of neuropathic pain.
CaV2.3 Mice show enhanced morphine analgesia and reduced tolerance in mice.
CaV3.1 neuropathic mice have reduced spontaneous pain and lowered mechanical and thermal hyperalgesia.
CaV3.2 endogenous lipoamino acids (anandamide-related molecules) produce strong thermal analgesia that is absent in CaV3.2 mutants
Ion channels involved in (synaptic) transmission
VOLTAGE DEPENDENT: CAV
- Pseudo-tetrameric structure
- Ca+ selective, voltage gated
- Modulatory subunits
- HVA: N (CaV2.2), L, P/Q, R
- LVA:T
- Pain relevant: N, (P/Q), T, 2d
Ion channels involved in (synaptic) transmission
VOLTAGE INDEPENDENT: NMDA/AMPA
- NMDA: N-Methyl-D-Aspartate, AMPA: Alpha-Amino Phosphonic Acid
- Heterotetramer of NR1/NR2 (NMDA), or GluR1-4 (AMPA)
- Mg2+ block under normal conditions (voltage dependent, only NMDA)
- Mixed cation selectivity
- Ligand-gated
- Slow (NMDA) or fast (AMPA) component of postsynaptic currents
Regulation of voltage-gated CaV channels
Presynaptic: CaV2.2: PRIALT TM
Postsynaptic: Kir -> activation (Flupirtin not approved)
Opioid receptor agonists
Morphine derivatives:
- Codeine
- Heroine
DHC derivatives:
- Oxycodon
- Hydrocodon
Pethidine
Methadone
DAMGO
Naloxon
Naltrexon -> upon opioid intoxication
Pain amelioration by opioids
Dorsal raphe -> Medulla -> PAG -> Spinal cord -> Locus coerulus
Side effects of opioids include:
* Addiction and tolerance
* Respiratory depression
* Nausea
* Vomiting
* Dizziness
* Mental clouding
* Dysphoria
* Pruritis
* Constipation
* Urinary retention
* Hypotension
* Delirium (rarely)
* Increased pain sensation after medication has worn off
Pain amelioration in anesthesia with opioids
-> Fentanyl
- Intravenous or transdermal administration
- Short time-to-peak analgesic effect
- Highly lipid-soluble -> fast equilibration between plasma and CSF (5 min)
- Reduces dose requirements for volatile agents
- t1/2 = variable, typically 3 - 4 h, accumulation occurs when high doses are used, and saturation of clearance
mechanisms occur - Hepatic metabolism, renal excretion
- Also used to treat severe! pain states
Pain amelioration in anesthesia with opioids
-> Remifentanil
- Similar analgesic activity as Fentanyl and Sufentanyl
- Intravenous administration
- Very short time-to-peak analgesic effect (1-1.5 min)
- Reduces dose requirements for volatile agents
- t1/2 =8-20min
- Metabolized by esterases, independent of hepatic metabolism
- Renal excretion
- Full recovery from all effects after about 15 min
Treatment of opioid addiction
-> Methadone
- Used for detoxification and maintenance treatment
- Chronic pain treatment
- Oral availability
- No respiratory depressant effects
- Lacks addiction liability
- Intermediate time-to-peak analgesic effect (10-20 min parenteral, 30-60 min oral)
- t1/2 =15-40h
- Extensive hepatic metabolism, renal excretion
- Can prolong the QT interval
N-type CaV channel antagonist Zinconotide (Prialt)
- Approved as medication for the treatment of advanced chronic pain.
- Can replace morphine.
- Difficult intrathecal application.
- Reduces neurotransmitter release in the spinal cord.
Bsp: Conus magus
N and P/Q type CaV channel antagonists
- Interacts with CaV alpha2 subunits.
- Approved for the treatment of neuropathic pain.
- Oral administration.
- Reduces neurotransmitter release in the spinal cord.
Bsp.: Gabapentin, Pregabalin
Summary
PERIPHERAL TERMINAL:
-> Noxious stimulus
1. TRPA1
2. TRPM8
3. ASIC
4. TRPV1-4
5. 5-HT
6. P2X
7. TRKA
8. GPCRs
-> Receptor potential
-> Action potential: Nav1.1, Nav1.6, Nav1.7, Nav1.8
DORSAL ROOT GANGLION:
action potential travels along axon
SPINAL CORD
1. AMPA
2. mGluR
3. NMDAR
