Rodent Models Of Pain Plasticity

In humans, tissue injury results in persistently increased pain sensation to mildly noxious stimuli (hyperalgesia) and pain perception to normally non-noxious stimuli (allodynia). These two forms of sensitization clearly fit within the definition of learning developed in the first chapter—persisting behavioral modification in response to an environmental signal. However, in this case, one mechanism contributing to the altered behavior is persisting production of chemical signals locally at the site of damage, which is in a sense not a memory event but a persisting "environmental" signal. However, it is clear that there are also pain-associated central plastic changes that occur in the CNS that alter perception of constant environmental signals.

Rodent model systems have allowed the delineation of two main mechanisms underlying persistent pain sensitization after tissue injury. First, primary sensory afferents known as AS and C fibers conveying peripheral pain signals to the central nervous system become sensitized. Physiologically, this sensitization manifests as a lower stimulus intensity threshold for firing and possibly increased transmitter release in the primary sensory neurons. Second, the CNS changes its processing of signals received from the periphery such that mildly noxious stimuli are coded more intensely and non-noxious stimuli are coded as noxious.

Rodents behaviorally exhibit the sequelae of peripheral and central sensitization in a manner analogous to human behavior. Simple reflexive behavior, such as paw withdrawal, allows experimenters to quantify and study responsiveness to stimuli in rodents. Analogous to human sensations, rodents with tissue injury withdraw their paws when given non-noxious stimuli such as warm heat or a light brush. Therefore, rodents provide a model system to dissect out the molecular mechanisms of sensitization through biochemistry and physiology in correlation with simple behavioral assays.

One of the main loci for central sensitiza-tion is the spinal cord dorsal horn, the first relay station for pain signals arriving from the periphery. This sensitization involves

BOX 3—cont'd RODENT MODELS OF PAIN PLASTICITY

changes in the coding of noxious signals and minimally must involve a change in synaptic strength or neuronal excitability— an interesting parallel to mechanisms of synaptic plasticity that we will be discussing later in the book in context of learning and memory.

Thermal pain thresholds in rats and mice are determined using an apparatus known as a Hargreave's radiant heat apparatus. In this test, the animals are allowed to move freely in small enclosures on an elevated glass plate. After a 1-hour acclimitization period, radiant heat is applied locally to one paw via a visible light source. The animals are not restrained; thus, when they feel discomfort, they withdraw the stimulated paw. The latency from onset of the stimulus to paw withdrawal is recorded, as an index of sensory perception and sensitization.

FIGURE 18 Acoustic startle and pre-pulse inhibition. (A) Acoustic startle in response to a 120-dB noise, assessed as the force exerted on an underlying footplate. (B) Effect of a pre-tone (sound intensity given in decibels) to diminish the magnitude of acoustic startle. Results are given as percent diminution of the force of the subsequent 120-dB startle response. Results shown are for C57Bl6 animals, mean ± SEM for n = 10 animals. Data courtesy of Coleen Atkins (10).

FIGURE 18 Acoustic startle and pre-pulse inhibition. (A) Acoustic startle in response to a 120-dB noise, assessed as the force exerted on an underlying footplate. (B) Effect of a pre-tone (sound intensity given in decibels) to diminish the magnitude of acoustic startle. Results are given as percent diminution of the force of the subsequent 120-dB startle response. Results shown are for C57Bl6 animals, mean ± SEM for n = 10 animals. Data courtesy of Coleen Atkins (10).

context it is of course important to have control data that animals are capable of normally perceiving aversive stimuli such as mild foot-shock. One test of nociception is assayed by placing the animals on a 55o C hotplate. Latency to lick the hind paw is measured (See Figure 19). In a similar test shock threshold sensitivity is measured by scoring animals for flinching, vocalizing and jumping behavior in response to 0.1-mA

foot shock increments (typically 0-1.5 mA, delivered for 1 second long each).

E. Vision Tests—Light-Dark Exploration and Visual Cliff

In many learning tasks, visual perception is an important variable. Two common tests of vision are light-dark exploration and the "visual cliff." It is important to

Shock Threshold

Shock Threshold

Flinching Jumping Vocalizing

FIGURE 19 Nociception behavior. (A) A hot plate test was used to compare PKC beta knockout animals (□) versus wild type (■) sensitivity to a noxious stimuli. Thermal nociception was measured on a 55°C hot plate as the latency to hind-paw lick. (B) As an additional control to the hot plate test, the shock threshold test was used to compare sensitivity to foot shock measured by the extent of flinching, jumping, or vocalizing to increasing foot shock intensities. Data courtesy of Coleen Atkins (5).

Flinching Jumping Vocalizing

FIGURE 19 Nociception behavior. (A) A hot plate test was used to compare PKC beta knockout animals (□) versus wild type (■) sensitivity to a noxious stimuli. Thermal nociception was measured on a 55°C hot plate as the latency to hind-paw lick. (B) As an additional control to the hot plate test, the shock threshold test was used to compare sensitivity to foot shock measured by the extent of flinching, jumping, or vocalizing to increasing foot shock intensities. Data courtesy of Coleen Atkins (5).

note that many inbred strains of rodents have poor vision and that in general rats and mice are not particularly "visual" creatures (limited stereopsis, for example). Overall, available visual tests for rodents are not very sensitive or sophisticated. One example of a visual task for rodents is light-dark exploration, which is used to asses an animal's ability to perceive light and dark. One typical variation consists of a polypropylene chamber (44 cm by 21 cm by 21 cm) unequally divided into two chambers by a black partition containing a small opening. The large chamber is open and brightly illuminated (800 lux), while the small chamber is closed and dark. Animals are placed into the illuminated side and allowed to move freely between the two chambers for 10 minutes—normal animals spend a majority of their time in the darkened chamber, as is expected for dark-preferring, nocturnal animals.

A second visual assessment paradigm is the visual cliff. In this task animals are placed on a see-through surface such as glass or plexiglass. This solid platform on one half has underneath it a solid surface and on the other half the air-space above the floor. Thus, a seeing animal perceives that one half of the chamber is a solid surface while the other half appears to be the open space above a large drop-off. Animals are placed on the "solid" surface and animals that can see rarely venture over the edge of the cliff. Non-seeing animals, of course, are unable to discern one area from the other as the tactile stimulus is a continuous smooth sheet.

The variety of control experiments described here can be combined into a general assessment battery consisting of open field test, rotating rod, acoustic startle, prepulse inhibition, hot plate, shock threshold, and visual assessment tasks. This battery of tests is quantitative and an excellent general screen for a wide variety of behaviors and sensory responses. Also typically included as control data are assessments of general physical parameters such as weight, temperature, coat appearance, and basic reflexes. Taken together, these tests serve as useful control experiments for experiments in which anatomical or molecular lesions are being used to probe for the role of specific structures or molecules in rodent behavioral learning and memory (11, 12).

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