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Pharmacological activation of 5-HT7 receptors reduces nerve injury-
induced mechanical and thermal hypersensitivity
9.22.10
PAIN is UNIVERSAL
YET, DIFFERENT for EVERYONE
ANIMAL MODELS for PAIN
5-HT7
• GPCR – Stimulates cAMP– Found in hypothalamus, thalamus, hippocampus,
cortex, blood vessels, intestines– Found in inverts and verts
• 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
• Functional roles– Thermoregulation– Learning and memory– Circadian rhythm– Endocrine regulation
5-HT7
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
METHODS and DESIGN
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
• 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
• 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
• 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
RESULTS
AS19 = 5-HT7 agonist
Mechanical Hypersensitivity
RESULTS
AS19 = 5-HT7 agonist
Thermal Hyperalgesia
RESULTS
SB-258719 = 5-HT7 antagonist
Mechanical Hypersensitivity
RESULTS
Thermal Hyperalgesia
SB-258719 = 5-HT7 antagonist
RESULTS
Mechanical Hypersensitivity
RESULTS
Thermal Hyperalgesia
RESULTS
RESULTS
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
SO CUTE!
Marcel the Shell with Shoes On!