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

Receptor typeFiber group Quality

Nociceptors Mechanical AδSharp,

pricking pain

Thermal and mechano-thermal Aδ

Sharp, pricking pain

Thermal and mechano-thermal C

Slow, burning pain

  Polymodal CSlow, burning

pain

Cutaneous and subcutaneous

mechanoreceptors

Meissner’s corpuscle Aβ Flutter

Pacinian corpuscles Aβ Vibration

Ruffini corpuscle AβSteady skin indentation

Merkel receptor AβSteady skin indentation

DRGSpinal

cord

Skin

Pain pathway II

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

Type of pain

Preclinical pain models

Ethical issuesLegislation: 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.

A. Acute pain:

B. Chronic pain:Inflammatory pain models

Neuropathic pain models

Phasic pain models

Tonic pain models

Preclinical pain models

Acute pain models

The hot plate test(according to Woolfe and McDonald,

1944)

The tail flick test

(according to D'Amour & Smith, 1941)

Phasic: short-duration stimulus-evoked models

Disease models

Pain-like behaviour

min after i.pl. injection

0 10 20 30 40 50 60 70

Paw

lick

ing

and

flinc

hing

(sec

/5 m

in)

0

50

100

150

200

250

saline 1.5% formalin

First phase

Second phase

Formalin test

Tonic: short-duration spontaneous models

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

• Read outs:– Mechanical allodynia– Mechanical hyperalgesia– Cold allodynia– Hot allodynia

Preclinical pain models

Mechanical allodyniavon Frey hair test

Thermal allodynia (hot)plantar test

Thermal allodyniacold plate test

Mechanical hyperalgesiaRandall-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

(Hegyi et al 2009)

Spinal cord dorsal horn