Helmut Segner Fish Nociception and pain A biological perspective

the trigeminal subnucleus caudalis (Dubin and Patapoutian 2010).
The peripheral axons branch into free un-encapsulated nerve endings
(Figure 1) that innervate distinct regions in skin and epidermis.
They can be arranged in non-corpuscular or corpuscular endings.
It is at these free nerve endings where the transduction of noxious
stimuli into an electrical signal takes place. The transduction occurs
through depolarizing of the peripheral membrane, a process
that involves a range of ion channelling receptor molecules (Basbaum
et al. 2009, Belmonte et al. 2009, Dubin and Patapoutian
2010). An example is provided by the TRPV1 receptor (capsaicin
receptor) which transduces noxious chemical stimuli (capsaicin,
contained in chilli pepper) – but also noxious heat stimuli – into an
action potential of the nociceptor membrane. Another well-studied
example of how a noxious stimulus is transduced into an action potential
is provided by the thermally gated Na + K + channels (Dubin
and Patapoutian 2010).
Once stimulated, nociceptors transmit the action potential along
the axon in the direction of the spinal cord. Transmission velocity
correlates directly to the diameter of the axons and whether or
not they are myelinated. The so-called C-fibers, which constitute
the majority of cutaneous nociceptive afferents, are unmyelinated
axons of small diameter (≤ 1µm), which are bundled in fascicles
ensheathed by non-myelinating Schwann cells. These axons support
conduction velocities of 0.4 to 1.5 m/s. In contrast, A-fibre
nociceptors (mostly Ad) are myelinated, thicker (2 µm) axons with
conduction velocities of 5 to 30 m/s. The Ad-fibers are responsible
for the initial fast-onset pain, while the C-fibres are responsible
for the deep, longer-lasting pain (St. John Smith and Lewin 2009,
Dubin and Patapoutian 2010). The intensity of the noxious stimulus
is encoded in the train – not in the amplitude – of the impulses.
Nociceptors can undergo sensitization, what means that their
threshold can change after the initial stimulation (Witt and Grifin
1962). This process is considered to be at least partly responsible
for increased pain sensitivity of injured tissue (primary hyperalgesia).
The ability to detect damaging environmental forces is a very
common, evolutionary conserved sensory trait of animal species
(St. John Smith and Lewin 2009). Given the fundamental role
nociception plays to protect animals from harmful impacts, the
evolutionary early development of nociceptive systems is hardly
surprising (Braithwaite 2010). Already bacteria show behavioural
responses to mechanical stimuli. Although as unicellular organisms
they cannot possess nociceptors, they possess mechanosensitive
ion channels, similar to those in the terminal endings of
nociceptors. In the animal kingdom, the first appearance of nervous
systems occurs within the phyla Cnidaria and Ctenophora. Although
they show a still fairly simple organization, they are already
able of sensing electrical and mechanical stimuli. True nociceptors,
finally, develop within the Bilateria, and here they were found in
all groups studied to date (St. John Smith and Lewin 2009).
2.2 Processing of nociceptive information at the spinal cord level
Nociceptive primary afferents from the skin, i. e. the small diameter
C-fibers and the medium diameter Ad-fibers terminate primarily
in the superficial laminae (I and II) of the dorsal horn of the spinal
cord (Millan 2002, Todd 2010). There is evidence that peptidergic
nociceptors, which express neuropeptides, target primarily projection
neurons and interneurons of lamina I, while non-peptidergic
nociceptors terminate primarily in lamina II. Collaterals of the
primary afferents terminate in deeper layers (laminae V/VI). Also
visceral nociceptors convey their information to the outer layers
of the dorsal horn, while nociceptive information from face and
teeth is transmitted through the branches of the Nervus trigeminus.
In the dorsal horn, the primary afferents stimulate numerous
ascending projection neurons which relay the information to the
brain. The principal neurotransmitter of the primary afferents is
glutamate, what implicates that primary afferents have an excitatory
effect on their postsynaptic targets.
The ascending neurons project to several brainstem and cortical
regions, many of them being interconnected and thus receiving
also indirect nociceptive inputs (see below). The main relay site
of nociceptive information in the brain is the thalamus (Millan
1999, Todd 2010). Neuroanatomy and organisation of ascending
projection pathways in mammals are highly complex, as the axons
originate from several laminae of the dorsal horn, and involve
diverse axon types and neurotransmitters (for details see Millan
18 Fish. Nociception and pain | Contributions to Ethics and Biotechnology
Fish. Nociception and pain | Contributions to Ethics and Biotechnology
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