Ratan K Banik, MBBS, PhD

1
Program No. 364.1 TrpV1 in primary afferent
terminals mediates plantar incision-induced heat
hyperalgesia

Na
Ca2
TrpV1
Na
depolarization, excitation
Ca2
substance P release

• Ratan K Banik, MBBS, PhD
• Department of Anesthesia, University of Iowa

2
Pain-like behaviors
Postoperative pain model (Brennan 1996)
Guarding behavior
? non-evoked pain? mechano-allodynia
Heat hyperalgesia
1 longitudinal incision in the rat or mouse
glabrous hindpaw skin
Mechano-allodynia
3

• Role of TrpV1 in postoperative pain model.
• Primary afferent TrpV1 is responsible for
  incisional heat hyperalgesia.
  
• Role of TrpV1 in primary afferent sensitization
  by incision.
  
• TrpV1 mediates heat sensitization of primary
  afferents after incisions.
  
• Role of TrpV1 in spontaneous activity of
  afferents after incision.
  
• After incision, TrpV1 is responsible for some
  spontaneous discharges, which may be C-fiber
  responses to bath temperature.

4
TrpV1 mediates heat hyperalgesia postoperative
heat hyperalgesia entirely eliminated by TrpV1
gene deletion
Heat pain
Guarding pain
Mechanical pain
1. Heat Latency of the withdrawal response to
radiant heat was measured 2. Cumulative pain sco
re in 1 hour period. 0full, 1 partial and 2
no weight bearing 3. Mechanical Lowest von Frey
hair that produced more than forty percent paw
withdrawal in five times application
4. N8 in each group, p
Repeated measure ANOVA
5
Primary afferent TrpV1 mediates postoperative
heat hyperalgesia postoperative heat
hyperalgesia entirely eliminated by perineural
capsaicin in tibial nerve
6

• Role of TrpV1 in postoperative pain model.
• Primary afferent TrpV1 is responsible for
  incisional heat hyperalgesia.
  
• Role of TrpV1 in primary afferent sensitization
  by incision.
  
• TrpV1 mediates heat sensitization of primary
  afferents after incisions.
  
• Role of TrpV1 in spontaneous activity of
  afferents after incision.
  
• After incision, TrpV1 is responsible for some
  spontaneous discharges, which may be C-fiber
  responses to bath temperature.

7

• Role of TrpV1 in postoperative pain model.
• Primary afferent TrpV1 is responsible for
  incisional heat hyperalgesia.
  
• Role of TrpV1 in primary afferent sensitization
  by incision.
  
• TrpV1 mediates heat sensitization of primary
  afferents after incisions.
  
• Role of TrpV1 in spontaneous activity of
  afferents after incision.
  
• After incision, TrpV1 is responsible for some
  spontaneous discharges, which may be C-fiber
  responses to bath temperature.

control
incision
8
Mouse glabrous skin nerve preparation first in
vitro recording of mouse glabrous skin afferents
9
TrpV1 mediates heat sensitization single and/or
multi- nerve fiber recording from Trpv1 knockout
and C57/Bl/6 mice glabrous skin 1-day after
plantar incision
/
-/-
40 ms
40 ms
1 V
49 oC
33 oC
10 s
10 s
1. Experiments were performed in a mouse glabrou
s skin nerve preparation 2. Heat 33 to 48C heat
ramp was delivered by a feedback controlled heat
stimulator
10
TrpV1 mediates heat sensitization absence of
incision induced heat-sensitization in TrpV1
knockouts
1. Experiments were performed in a mouse glabrou
s skin nerve preparation 2. Heat 33 to 48C heat
ramp was delivered by a feedback controlled heat
stimulator 3. N24 for wild type and N22 for kno
ck out animals
11

• Role of TrpV1 in postoperative pain model.
• Primary afferent TrpV1 is responsible for
  incisional heat hyperalgesia.
  
• Role of TrpV1 in primary afferent sensitization
  by incision.
  
• TrpV1 mediates heat sensitization of primary
  afferents after incisions.
  
• Role of TrpV1 in spontaneous activity of
  afferents after incision.
  
• After incision, TrpV1 is responsible for some
  spontaneous discharges, which may be C-fiber
  responses to bath temperature.

12

• Role of TrpV1 in postoperative pain model.
• Primary afferent TrpV1 is responsible for
  incisional heat hyperalgesia.
  
• Role of TrpV1 in primary afferent sensitization
  by incision.
  
• TrpV1 mediates heat sensitization of primary
  afferents after incisions.
  
• Role of TrpV1 in spontaneous activity of
  afferents after incision.
  
• After incision, TrpV1 is responsible for some
  spontaneous discharges, which may be C-fiber
  responses to bath temperature.

13
Spontaneous activity of C-fibers much less
spontaneously discharging neurons in TrpV1
knockouts
Heat-sensitive fibers
p
-spontaneously discharging C-fibers
1. Heat sensitive fibers, N15 for / and N13
for -/-
2. P
14
Spontaneous activity heat sensitivity
spontaneous discharging neurons have decreased
heat threshold
48
44
Heat
(oC)
40
36
32
s
10
1. The heat response threshold of this fiber is
35C. 2. The experiment was performed in a mouse g
labrous skin nerve preparation
15
Cooling reduces spontaneous activity bath
temperature may be responsible for spontaneous
discharge
1. The heat response threshold of this fiber is
35C. 2. The experiment was performed in a mouse g
labrous skin nerve preparation
16
Cooling reduces spontaneous activity bath
temperature may be responsible for spontaneous
discharge
Heat-sensitive fibers
Effects of cooling on spontaneous discharges
p
Disappeared
No effect
Not applied
-spontaneously discharging C-fibers
1. Heat sensitive fibers, N15 for / and N1
3 for -/-
2. P
17

• Role of TrpV1 in postoperative pain model.
• Primary afferent TrpV1 is responsible for
  incisional heat hyperalgesia.
  
• Role of TrpV1 in primary afferent sensitization
  by incision.
  
• TrpV1 mediates heat sensitization of primary
  afferents after incisions.
  
• Role of TrpV1 in spontaneous activity of
  afferents after incision.
  
• After incision, TrpV1 is responsible for some
  spontaneous discharges, which may be C-fiber
  responses to bath temperature.

18

• Acknowledgement
• Timothy J. Brennan, MD, PhD
• Alberto Subieta, BS
• University of Iowa PIG (Pain Interest Group)
  directed by Gerald F. Gebhart, PhD and Donna L.
  Hammond, PhD