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Pharmacological activation of 5-HT 7 receptors reduces nerve injury-induced mechanical and thermal hypersensitivity 9.22.10
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Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

Jan 20, 2016

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Moris French
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Page 1: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

Pharmacological activation of 5-HT7 receptors reduces nerve injury-

induced mechanical and thermal hypersensitivity

9.22.10

Page 2: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

PAIN is UNIVERSAL

Page 3: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

YET, DIFFERENT for EVERYONE

Page 4: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

ANIMAL MODELS for PAIN

Page 5: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

5-HT7

• GPCR – Stimulates cAMP– Found in hypothalamus, thalamus, hippocampus,

cortex, blood vessels, intestines– Found in inverts and verts

Page 6: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

• Receptor signaling– Activates ERK through Ras monomemric GTPase-

dependent mechanism– But independent from PKA through cAMP-

activated guanine nucleotide exchange factor• E.g. stimulates ERK in hippocampal neurons affect

hippocampal function and mood regulation

5-HT7

Page 7: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

• Functional roles– Thermoregulation– Learning and memory– Circadian rhythm– Endocrine regulation

5-HT7

Page 8: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

METHODS and DESIGN

• Male, 6-8 week old CD1 mice

• Housed in groups of 5 with water and food

• Maintained in 21 degrees C with 12 hr light/dark cycles

Page 9: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

METHODS and DESIGN

Page 10: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

METHODS and DESIGN• Neuropathic pain model: partial sciatic

nerve ligation– Partial injury to the SN at mid-thigh

level– Common SN exposed

• Tied tight ligatures around approx 33-50% of diameter of SN

• Ligature enclosed outer 1/3-1/2 SN, while rest of SN (inner 2/3-1/2) was left alone

• Muscle stitched up – Controls had same procedure w/o

ligation

Page 11: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

• Mechanical hypersensitivity– Quantified by pressure TH

eliciting withdrawal of ipsilateral hindpaw through von Frey

• Thermal hyperalgesia– Quantified by hindpaw

withdrawal latency in response to radiant heat (a mobile infared photobeam) in plantar test

• Motor coordination– Assess by an automated rotarod

METHODS and DESIGN

Page 12: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

• Experimental approach (acute admin)– 2 day habituation period, then pre-surgery

pretest– Surgery (sham or nerve ligation)– Post-surgery responses of vehicle mice tested

at day 10– Days 11-13, mice were treated with three

different doses (.1, 1, 10mg/kg) of agonist AS-19 or antagonist SB-258719

• Day 11 – antagonist• Day 12 – agonist• Day 13 – combo

– Day 14, mice given vehicle and post-treatment responses were assessed

METHODS and DESIGN

Page 13: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

• Experimental approach (repeated admin)– Effect of agonist E-57431 on development

of neuropathic pain behaviors– 2 day habituation period, then pre-

surgery pretest of von Frey and plantar tests for 15 min intervals between each test

– Surgery (sham or nerve ligation)– E-57431 or vehicle started the day of

surgery to day 11– Tested on days 3, 6, and 10– All mice received vehicle on days 12, 15,

and 20 and were tested

METHODS and DESIGN

Page 14: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

RESULTS

AS19 = 5-HT7 agonist

Mechanical Hypersensitivity

Page 15: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

RESULTS

AS19 = 5-HT7 agonist

Thermal Hyperalgesia

Page 16: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

RESULTS

SB-258719 = 5-HT7 antagonist

Mechanical Hypersensitivity

Page 17: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

RESULTS

Thermal Hyperalgesia

SB-258719 = 5-HT7 antagonist

Page 18: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

RESULTS

Mechanical Hypersensitivity

Page 19: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

RESULTS

Thermal Hyperalgesia

Page 20: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

RESULTS

Page 21: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

RESULTS

Page 22: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

DISCUSSION

• Activation of 5-HT7 receptors (agonist AS-19) dose-dependent inhibition of mechanical hypersensitivity and thermal hyperalgesia

• Co-admin with antagonist, SB-258719, blocked effects

• Overall effect was anti-nociceptive and maintained throughout treatment period

Page 23: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

SO CUTE!

Page 24: Pharmacological activation of 5-HT 7 receptors reduces nerve injury- induced mechanical and thermal hypersensitivity 9.22.10.

Marcel the Shell with Shoes On!