NEUROVASCULAR MEDICINE - Pursuing Cellular Longevity for Healthy Aging Part 4 pot

168 PATHWAYS OF CLINICAL FUNCTION AND DISABILITY

forebrains have been characterized (Zhuo, Gebhart

1990a, 1990b, 1991, 1992, 1997; Calejesan, Kim, Zhuo

2000). Biphasic modulation of spinal nociceptive trans￾mission from the RVM, perhaps refl ecting the differ￾ent types of neurons identifi ed in this area, offer fi ne

regulation of spinal sensory thresholds and responses.

While descending inhibition is primarily involved in

regulating suprathreshold responses to noxious stimuli,

descending facilitation reduces the neuronal thresh￾old to nociceptive stimulation (Zhuo, Gebhart 1990a,

1990b, 1991, 1992, 1997). Descending facilitation has a

general impact on spinal sensory transmission, induc￾ing sensory inputs from cutaneous and visceral organs

(Zhuo, Sengupta, Gebhart 2002; Zhuo, Gebhart 2002;

Zhuo 2007) (Fig. 6.13). Descending facilitation can

be activated under physiological conditions, and one

physiological function of descending facilitation is to

enhance the ability of animals to detect potential dan￾gerous signals in the environment. Indeed, neurons

in the RVM not only respond to noxious stimuli, but

also show “learning”-type changes during repetitive

noxious stimuli. More importantly, RVM neurons can

undergo plastic changes during and after tissue injury

and infl ammation.

ACC-Induced Facilitation

It is well documented that the descending endogenous

analgesia system, including the PAG and RVM, plays

an important role in modulation of nociceptive trans￾mission and morphine- and cannabinoid-produced

analgesia. Neurons in the PAG receive inputs from

different nuclei of higher structures, including the

cingulated ACC. Electrical stimulation of ACC at high

intensities (up to 500 µA) of electrical stimulation

did not produce any antinociceptive effect. Instead,

at most sites within the ACC, electrical stimulation

produced signifi cant facilitation of the TF refl ex (i.e.

decreases in TF latency). Activation of mGluRs within

the ACC also produced facilitatory effects in both

anesthetized rats or freely moving mice (Calejesan,

Kim, Zhuo 2000; Tang et al. 2006). Descending facil￾itation from the ACC apparently relays at the RVM

(Calejesan, Kim, Zhuo 2000) (see Fig. 6.14).

Descending Facilitation Maintains

Chronic Pain

Descending facilitation is likely activated after

the injury, contributing to secondary hyperalge￾sia (Calejesan, Ch’ang, Zhuo 1998; Robinson et al.

2002b). Blocking descending facilitation by lesion of

the RVM or spinal blockade of serotonin receptors

is antinociceptive (Urban, Gebhart 1999; Porreca,

Ossipov, Gebhart 2002; Robinson et al. 2004). The

descending facilitatory system therefore serves as a

30 mmHg

30 mmHg

Control

10 Hz

10 s

Electrical stimulation

A B

C

Glutamate 600

Total no.

imps/20 s

Response to distention

Glutamate

(5 nmoles)

400

200

0

c stim

25 µA

P 10.30

NGC NRM

LC

Sp5

NPGCL

1 mm

Pyr

NGCα

01 4

Time (min)

7 10

Figure 6.13 Descending facilitation of spinal visceral pain transmission. Example of facilitation of spinal visceral transmission produced by

electrical stimulation and glutamate in the nucleus raphe magnus (NRM). (A) Peristimulus time histograms (1-second binwidth) and cor￾responding ocillographic records in the absence (top histograms) and presence (bottom histograms) of electrical stimulation (25 µA) and

glutamate (5 nmoles) given in the same site in NRM. The intensity and duration of colorectal distension is illustrated below; the period of

electrical stimulation (25 seconds) is indicated by the arrows. (B) Summary of the data illustrated in (A) and time course of effect of gluta￾mate given in NRM. The point above c represents the response to 30-mmHg colorectal distension; the point above stimulation represents

the response to the same intensity of distension during stimulation in NRM. (C) Site of stimulation and injection of glutamate.

Chapter 6: Neurobiology of Chronic Pain 169

7

A B

C

6

5

4

3

–15

30

20

10

–10

–20

Spinal cord

+: 5-HT

RVM

ACC

Descending

facilitation

0

–10

–5 0

5

10

Time, min

Pre CNQX

*

Recovery

TF latency, s

Facilitation (%)

CNQX (0.5 µL)

15

20

25

30

35

40

45

50

Without stimulation

Stimulation at 50 µA

Figure 6.14 ACC controls RVM-generated descending facilitation. (A) A model shows supraspinal control of RVM-generated descending

facilitation of spinal nociception by ACC) neurons. (B) An example illustrates that CNQX microinjection into the RVM reversibly blocks

facilitation of the TF refl ex produced by electrical stimulation at a site within the ACC; TF response latencies measured without stimula￾tion were represented by open squares. TF latencies measured with stimulation were represented by fi lled squares; (C) Summary data

showing mean facilitation (% of control) before CNQX injection into the RVM (Pre); after (within 10 minutes); and 30 minutes after

(30 min post).

double-edged blade in the central nervous system. On

one hand, it allows neurons in different parts of the

brain to communicate with each other and enhances

sensitivity to potentially dangerous signals; on the

other hand, prolonged facilitation of spinal nocicep￾tive transmission after injury speeds up central plastic

changes related to chronic pain (Table 6.3).

CONCLUSIONS AND FUTURE

DIRECTIONS

Finally, I would like to review and propose three key

cellular models for future investigations of chronic

pain. I would like to emphasize that integrative

experimental approaches are essential for future

studies to avoid the misleading discoveries; work

at different sensory synapses are equally critical

such as spinal cord synapses, cortical synapse, and

brainstem synapses that dictate descending facilita￾tory and inhibitory modulations. Table 6.4 summa￾rizes likely key mechanisms for chronic pain. They

include

1. Plasticity of sensory synaptic transmission: excitatory

(glutamate) and inhibitory (GABA, Gly) transmission

2. Anatomic structural changes: synaptic reorganiza￾tion (e.g. changes in spines), cortical reorganization,

neuronal phenotype switch, cortical gray matter loss

3. Long-term alteration in descending modulation:

enhanced descending facilitation or loss of tonic

descending inhibitory infl uences

In summary, progress made in basic neurobiology

investigations has signifi cantly helped us understand

the fundamental mechanism for pain or physiologi￾cal pain processes, both at the peripheral spinal cord

level and at the cortical level. Studies of central plas￾ticity, including LTP/LTD in sensory synapses, start to

provide useful cellular models for our understanding

of chronic pain. Novel mechanisms revealed at molec￾ular and cellular levels will signifi cantly affect our

future approaches to search and design novel drugs

for treating chronic pain in patients.

Acknowledgment I thank funding supports from

the EJLB-CIHR Michael Smith Chair in Neurosciences

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and Mental Health in Canada, CIHR operating grants,

Canada Research Chair, and NeuroCanada Brain repair

program.

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Table 6.4 Proposed Key Neurobiological Mechanisms for Chronic Pain

Proposed Model Synaptic Consequences Key References

Plasticity of synaptic transmission

Silent synapse

LTP

Loss of LTD

Microglia disinhibition

Recruit AMPA responses into NS

specifi c cells

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GluR1 mediated LTP

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Fail to depotentiate enhanced responses

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Table 6.3 Comparison of Endogenous Facilitation and Analgesia Systems

Descending Facilitation Descending Analgesia

Central origin ACC; RVM PAG; RVM

Neurotransmitter Glutamate; neurotension Glutamate; opioids

Stimulation intensity 5–25 µA 50–100 µA

Stimulation–response

Function (SRF)

Reduced threshold Reduced peak response without

affecting threshold

Response latency 200 ms 90 ms

Laterality Bilateral Bilateral

Spinal pathways Ventrolateral funiculi (VLF)/ventral

funiculi (VF)

Dorsolateral funiculi (DLF)

Spinal neurotransmitter 5-HT Ach; NE; 5-HT

Synaptic mechanism AMPA receptor traffi cking

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EPSCs

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Nociceptive

Mechanical

Thermal

Non-nociceptive

Nociceptive

Mechanical

Thermal

Origin of sensory inputs Somatosensory

Visceral

Somatosensory

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