0006-Ch03.pdf

5-HT Receptors and

the Neuromodulatory

Control of Spinal

Cord Function

Shawn Hochman, Sandra M. Garraway,

David W. Machacek, and Barbara L. Shay

CONTENTS

3.1 Overview

3.2 Background

3.2.1 Brainstem Serotonergic Neuronal Populations with Projections

to Spinal Cord

3.2.2 5-HT Receptors Found in the Spinal Cord

3.2.2.1 5-HT 1 Receptors

3.2.2.1.1 Anatomy

3.2.2.1.2 Pharmacology

3.2.2.2 5-HT 2 Receptors

3.2.2.2.1 Anatomy

3.2.2.2.2 Pharmacology

3.2.2.3 5-HT 3 Receptors

3.2.2.3.1 Anatomy

3.2.2.3.2 Pharmacology

3.2.2.4 5-HT 4–7 Receptors

3.2.2.4.1 5-HT Effects Possibly Mediated

by 5-HT 7 Receptor Activation

3.3 5-HT Receptor Subtype-Selective Effects on Spinal Cord Function:

New Findings

3.3.1 5-HT 1A and 5-HT 7 Receptor Subtypes Modulate Sensory

Transmission in Deep Dorsal Horn Neurons

3.3.1.1 Background

3.3.1.2 Experimental Observations

3.3.2 5-HT 1A/1B Receptors Facilitate the Induction of Long-Term

Depression

3.3.2.1 Background

3.3.2.2 Experimental Observations

3.3.3 5-HT 2C Receptors Induce a Long-Lasting Facilitation

of Spinal Reﬂexes

3.3.3.1 Background

3.3.3.2 Experimental Observations

3.3.3.2.1 5-HT-Induced Long-Lasting

Reﬂex Facilitation

3.3.3.2.2 5-HT-Induced Long-Lasting Facilitation

of Synaptic Strength in Spinal Neurons

3.3.4 5-HT 7 Receptor Activation May be Essential for 5-HT-Induced

Locomotor Rhythmogenesis

3.3.4.1 Background

3.3.4.2 Experimental Observations

3.3.4.2.1 5-HT 7 Receptor Pharmacology

and Locomotion

3.3.4.2.2 5-HT 7 Receptor Immunolabeling

and the Locomotor CPG

3.4 Comparison of 5-HT Actions to Other Monoamines

3.4.1 Evidence that Brainstem Monoamine Transmitters

have Common Cellular Neuromodulatory Actions

3.4.1.1 Background

3.4.1.2 Experimental Observations

3.5 Concluding Remarks

References

ABSTRACT The purpose of this chapter is to present some recent experimental

data obtained in our laboratory that provide new insights and suggest new hypotheses

on the organization of serotonergic systems within the mammalian spinal cord. Our

proposed conceptual framework for understanding 5-hydroxytryptamine (5-HT;

serotonin) function incorporates the existence of multiple descending serotonergic

systems and multiple spinal serotonin receptor subtypes.

3.1 OVERVIEW

Investigations on the spinal actions of 5-HT can be partitioned into three areas:

sensory mechanisms, motor control, and autonomic function. While there is clearly

a strong descending serotonergic control of spinal autonomic function, 1,2 this will

not be explored here. Studies on 5-HT and sensory mechanisms have focused on

the modulation of nociception, demonstrating the actions of 5-HT and 5-HT receptor-

selective ligands on dorsal horn neurons and on nocisponsive reﬂexes. 3–7 Studies of

5-HT in motor control have focused on the modiﬁability of motoneuron function,

particularly with respect to the activation of persistent inward currents, 8–10 as well

as those concerned with the initiation and modulation of motor behaviors such as

locomotion. 11–17 Motoneurons are relatively easy to target experimentally, and con-

sequently have provided important information on the actions of 5-HT at the cellular

level within the spinal cord. 18–21 However, spinal motoneurons comprise a very small

fraction of the neurons within the spinal cord, and the spinal networks that receive

descending commands and coordinate sensorimotor activities are pre-motoneuronal.

For example, in rats, 5-HT can activate the spinal locomotor circuitry, yet the

mechanism by which 5-HT is capable of recruiting the locomotor central pattern

generator (CPG) is almost completely unknown. Clearly, further insight on 5-HT

function requires study of the actions of 5-HT on spinal neurons engaged in the

control of both segmental and ascending sensorimotor information processing. In

this regard, we can particularly thank the efforts of Jankowska’s 22,23 and Willis’

groups 24–26 for undertaking such studies on identiﬁed neuronal populations in vivo .

Physiologically, the spinal actions of 5-HT have been segregated into a modu-

latory depression of sensory input and a facilitation of motor output. These effects

and the activity patterns of serotonergic neurons during various sensory and motor

behaviors have resulted in a heuristic hypothesis on 5-HT and motor control for-

warded by Jacobs and Fornal. 27 They hypothesized that

the primary function of 5-HT neurons is to facilitate motor output … In an ancillary

manner, the system acts to inhibit sensory information processing … When the 5-HT

system is inactivated, these relationships are reversed: motor output is disfacilitated

and sensory information processing is disinhibited.

The appeal of this hypothesis is in its attempt to address the breadth of CNS

behaviors whose activities are related to 5-HT. Accordingly, serotonergic systems

have been shown to exert profound modulatory actions in spinal cord by inhibiting

sensory systems and facilitating motor systems. 28,29 In support of this, descending

serotonergic activity can powerfully inhibit nociceptive information in neurons by

activation of serotonergic 5-HT 1 and 5-HT 3 receptors. 30–32 Conversely, with respect

to motor control, 5-HT is released in spinal cord during locomotion, 14,17 and activa-

tion of spinal cord serotonergic receptors have been reported to initiate and modulate

locomotor patterns 11–13,15,16 and increase motoneuron excitability. 18,19,33

However, it is now clear that 5-HT can have actions that oppose the general

hypothesis forwarded by Jacobs and Fornal, 27 as stimulation of the nucleus reticularis

gigantocellularis has pronociceptive actions that involve serotonergic activity. 34,35

These studies demonstrate that while particular serotonergic systems originating in

the brainstem are responsible for the pro-motor, anti-sensory modulatory responses,

other serotonergic systems perform outside the aforementioned general hypothesis

on 5-HT function.

Given the multiple serotonergic bulbospinal projections described below (3.2.2)

and the many 5-HT receptor subtypes found in the spinal cord (3.2.3 below), it is

likely that no simple hypothesis on the actions of 5-HT in the spinal cord can account

for all the behaviors modulated by 5-HT. Rather, the actions of 5-HT must be

addressed in the context of: (i) the several brainstem regions that project descending

serotonergic ﬁbers to the spinal cord, (ii) the several 5-HT metabotropic receptor

subtypes with differing actions on signal transduction, and (iii) the different topo-

graphic distributions of both distinct serotonergic systems and receptor subtypes.

In order to account for the plethora of bulbospinal serotonergic systems and

receptor subtypes, we suggest an alternate perspective on the spinal actions of 5-HT.

The viewpoint taken is that the spinal cord functions in several distinct behavioral

modulatory states. Motor states would include those associated with locomotion,

reﬂex activity, and posture. Sensory states would include normal, suppressed, and

ampliﬁed sensory input states. We propose that each state is regulated by a distinct

bulbospinal modulatory system, and that each serotonergic system exerts a broad

inﬂuence on spinal cord function by targeting speciﬁc metabotropic receptor sub-

types that alter cellular signal transduction pathways throughout a broad spinal projec-

tion territory. Hence, just as there are several brainstem regions with descending sero-

tonergic projections (see 3.2.2 b elow), so are there several different modulatory states

that 5-HT can regulate in the spinal cord. We forward the following hypothesis:

Hypothesis #1. Behaviourally relevant sensory and motor acts are modulated by

brainstem centers that recruit bulbospinal aminergic systems. Distinct serotonergic

systems in the brainstem reconﬁgure spinal neural networks into various functional

states. Part of their ability to control separate functional systems is based on the

postsynaptic properties of 5-HT receptor subtypes.

Evidence supporting the existence of 5-HT receptor subtype-selective control

of separate spinal cord sensory and motor states is provided below in 3.3.

Receptor- and voltage-gated channels are dynamically modulated through the

phosphorylation and dephosphorylation reactions initiated via signal transduction

pathways. 36 5-HT interacts with these systems via numerous metabotropic receptor

subtypes and presumably modiﬁes many membrane channels so that the entire

physiological performance of a cell, as well as its network interactions, can be

reconﬁgured. 36–38 As distinct metabotropic receptor subtypes alter activity in signal

transduction pathways differently, activation of distinct 5-HT receptors should have

different physiological consequences on spinal cord function.

Hypothesis #2. Metabotropic receptor subtypes that increase phosphorylation reactions

(5-HT 2 , 5-HT 4,6,7 ) are net excitatory and would be found on speciﬁc cellular and

synaptic locations that favor facilitated activity while receptor subtypes which inhibit

phosphorylation reactions (5-HT 1 ) are net inhibitory and would be located at synaptic

and cellular regions targeted for depression (see Table 3.1 ). Distinct metabotropic

receptor subtypes are involved in the control of different spinal cord states.

This hypothesis is broadly consistent with the numerous actions of 5-HT in the

CNS 39 and represents a logical extension of the trend observed by Aghajanian et al. 40

regarding the actions of 5-HT 1 and 5-HT 2 receptor subtypes. The notion that different

5-HT receptor subtypes control different behavioral states is not new and has a rich

history in relation to a variety of brain disorders. For example, the 5-HT 1 family of

receptors have been implicated in depression (5-HT 1A ) and migraine (5-HT 1B and

5-HT 1D ), the 5-HT 2 receptors in psychosis (5-HT 2A ), anxiety, feeding, and seizures

(5-HT 2C ), and the 5-HT 3 receptors in emesis. We assert that a similar dissection of

5-HT receptor subtype with distinct functions occurs in the spinal cord.

TABLE 3.1

Monoamine Receptor Subtypes and Their Effects

on Signal Transduction Pathways

Effector Coupling

↑

cAMP

↑

IP3/DAG

↓

cAMP

Ionotropic

Serotonin

5-HT 4,6,7

5-HT 2A–C

5-HT 1A,B,D,E,F

5-HT 3

Noradrenaline

β 1–3

α 1A,B,D

α 2A–D

Dopamine

D 1,5

D 2–4

Note : The 5-HT 2C receptor was previously referred to as the 5-HT 1C receptor.

The primary purpose of this chapter is to provide new experimental data obtained

in our laboratory that support the aforementioned hypotheses ( 3.3 ) . However, in

order to permit a broad appreciation of the serotonergic systems in the spinal cord,

we ﬁrst provide a general review of the bulbospinal serotonergic descending systems

(3.2.1) and the 5-HT receptor subtypes found in the spinal cord ( 3.2.2 ) .

3.2 BACKGROUND

3.2.1 B RAINSTEM S EROTONERGIC N EURONAL P OPULATIONS

WITH P ROJECTIONS TO S PINAL C ORD

It has been known since the landmark studies of Dahlström and Fuxe 42,43 that the

brainstem contains serotonergic nuclei that project to the spinal cord. These projec-

tions are diffuse and originate from several brainstem monoaminergic nuclei. 42,44

Steinbusch 45 demonstrated that serotonergic ﬁbers extensively innervate the spinal

cord of the rat, with the highest density of innervation found in the ventral horn and

high to medium density found at all levels of the dorsal horn. Similarly, Marlier

et al. 46 reported high to intermediate concentrations of serotonergic ﬁbers innervating

the spinal cord dorsal horn of the rat. Simply stated, serotonergic ﬁbers project

throughout the spinal cord gray matter.

The absence of distinct boundaries between 5-HT-containing neurons within

raphe nuclei and those found in the surrounding reticular formation has led to an

alphanumeric classiﬁcation of brainstem 5-HT-containing neurons into 9 groups

(B1–B9). 47 B1–B4 cell groups differentiate embryologically from a single caudal

group, while B5–B9 neurons develop from a rostral cell cluster. 48 In rat, 5-HT-

containing neurons of the B1–B4 cell groups possess descending projections to the

spinal cord and contain the following cytoarchitectural regions: raphe pallidus (B1),

caudal ventrolateral medulla (B1), raphe obscurus (B2), raphe magnus (B3), rostral

ventrolateral medulla (B3), lateral paragigantocellularis reticularis (B3), and the

central gray of the medulla oblongata (B4). 47 In addition, it appears that 5-HT-

containing neurons from the B5–B9 cell group have descending projections to the

cervical spinal cord. 49 Thus, the brainstem contains numerous distinct topographic

populations of serotonergic neurons with projections to spinal cord.

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