Cannabinoid system physiological effects
•
•
•
•
•
•
•
Motor impairement
Memory impairement
Catalepsy
Temperature decrease
Analgesia
Pressure modification
Immune suppression/stimulation
Definition of pain and nociception
• Pain is “An unpleasent sensory and
emotional experience associated with actual
or potential tissue damage, or described in
term of such damage” IASP 1979
• Nociception is referred to the reception in
the central nervous system of signals
triggered by the activation of specialized
receptors called nociceptors
Pain pathway I
Fiber
group
Quality
Mechanical
Aδ
Sharp,
pricking pain
Thermal and
mechano-thermal
Aδ
Sharp,
pricking pain
Thermal and
mechano-thermal
C
Slow, burning
pain
Polymodal
C
Slow, burning
pain
Meissner’s
corpuscle
Aβ
Flutter
Pacinian corpuscles
Aβ
Vibration
Ruffini corpuscle
Aβ
Steady skin
indentation
Merkel receptor
Aβ
Steady skin
indentation
Receptor type
Nociceptors
Cutaneous and
subcutaneous
mechanoreceptors
Skin
Spinal
cord
DRG
Pain pathway II
Type of pain
Pain grouping
Etiology
Neuropathic
Painful diabetic neuropathy (PDN)
HIV-related neuropathic pain
Postherpetic neuralgia (PHN)
Acute
Postoperative pain
Visceral
Irritable bowel syndrome
Chronic pelvic pain
Cancer related pain
Severe pain
Metastatic bone pain
Neuropathic pain (caused by nerve
injury and chemotherapic agents)
Breakthrough pain
Musculoskeletal pain
Painful osteoarthritis
Painful rheumatoid arthritis
Chronic lowback pain
Fibromyalgia
Headache
Migraine
Chronic daily headache
Preclinical pain models
Ethical issues
Legislation: Procedures involving animals and their care must be
conducted in conformity with the institutional guidelines, in
compliance with national and international law
• Experiments involving the study of pain on conscious animals must be
reviewed by a specific committee;
• Is forbidden the use of animals paralyzed with a neuromuscular blocking
agent without a general anesthetic or an appropriate surgical procedure
that eliminates sensory awareness;
• The duration of experiments must be as short as possible, and the number
of animals involved must be kept to the minimum.
Preclinical pain models
Phasic pain models
A. Acute pain:
Tonic pain models
Inflammatory pain models
B. Chronic pain:
Neuropathic pain models
Acute pain models
Phasic: short-duration stimulus-evoked models
The hot plate test
(according to Woolfe and McDonald, 1944)
The tail flick test
(according to D'Amour & Smith, 1941)
Disease models
Tonic: short-duration spontaneous models
Pain-like behaviour
Formalin test
Paw licking and flinching (sec/5 min)
First phase
250
Second phase
200
150
100
50
0
0
10
20
30
40
50
min after i.pl. injection
saline
1.5% formalin
60
70
Chronic pain models
1. Metabolic disfunction
STZ-induced diabetic neuropathy
2. Cancer pain
Vincristine-induced neuropathic pain
3. Infectious disease
Varicella zoster virus-induced
neuropathy
4. Neuropathic pain
Surgical manipulation of sciatic nerve
5. Post-tissue injury
Injection of an irritant into a joint or
hind paw
6. Inflammatory pain model
Injection of CFA
Neuropathic pain models
Preclinical pain models
Thermal allodynia (hot)
plantar test
• Read outs:
–
–
–
–
Mechanical allodynia
Mechanical hyperalgesia
Cold allodynia
Hot allodynia
Mechanical allodynia
von Frey hair test
Thermal allodynia
cold plate test
Mechanical hyperalgesia
Randall-Selitto
Cannabinoid and nociception
Potential targets for intervention
• CB1 and CB2 receptors:
– Use of agonists to induce analgesia.
• Endocannabinoids internalization:
– Blockade of the transporter to elevate the
extracellular level of endocannabinoids.
• Endocannabinoids degradation
– Blockade of the endocannabinoid degrading
enzymes (FAAH and/or MAGL) to elevate
endocannabinoid extracellular level.
CB1 and nociception
CB1 localization
Spinal cord dorsal horn
(Hegyi et al 2009)