The study of pain in awake animals raises ethical, philosophical, and technical problems. We review the ethical standards for studying pain in animals and emphasize that there are scientific as well as moral reasons for keeping to them. Philosophically, there is the problem that pain cannot be monitored directly in animals but can only be estimated by examining their responses to nociceptive stimuli; however, such responses do not necessarily mean that there is a concomitant sensation. The types of nociceptive stimuli (electrical, thermal, mechanical, or chemical) that have been used in different pain models are reviewed with the conclusion that none is ideal, although chemical stimuli probably most closely mimic acute clinical pain. The monitored reactions are almost always motor responses ranging from spinal reflexes to complex behaviors. Most have the weakness that they may be associated with, or modulated by, other physiological functions. The main tests are critically reviewed in terms of their sensitivity, specificity, and predictiveness. Weaknesses are highlighted, including 1) that in most tests responses are monitored around a nociceptive threshold, whereas clinical pain is almost always more severe; 2) differences in the fashion whereby responses are evoked from healthy and inflamed tissues; and 3) problems in assessing threshold responses to stimuli, which continue to increase in intensity. It is concluded that although the neural basis of the most used tests is poorly understood, their use will be more profitable if pain is considered within, rather than apart from, the body's homeostatic mechanisms.

Animal Models of Nociception

This paper reviews the recent advances in knowledge of brainstem mechanisms related to craniofacial pain. It also draws attention to their clinical implications, and concludes with a brief overview and suggestions for future research directions. It first describes the general organizational features of the trigeminal brainstem sensory nuclear complex (VBSNC), including its input and output properties and intrinsic characteristics that are commensurate with its strategic role as the major brainstem relay of many types of somatosensory information derived from the face and mouth. The VBSNC plays a crucial role in craniofacial nociceptive transmission, as evidenced by clinical, behavioral, morphological, and electrophysiological data that have been especially derived from studies of the relay of cutaneous nociceptive afferent inputs through the subnucleus caudalis of the VBSNC. The recent literature, however, indicates that some fundamental differences exist in the processing of cutaneous vs. other craniofac...

Acute and Chronic Craniofacial Pain: Brainstem Mechanisms of Nociceptive Transmission and Neuroplasticity, and Their Clinical Correlates

Burstein, Rami, Hiroyoshi Yamamura, Amy Malick, and Andrew M. Strassman. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neur...

Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons.

Calcitonin gene-related peptide (CGRP) is a key mediator in primary headaches including migraine. Animal models of meningeal nociception demonstrate both peripheral and central CGRP effects; however, the target structures remain unclear. To study the distribution of CGRP receptors in the rat trigeminovascular system we used antibodies recognizing two components of the CGRP receptor, the calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 1 (RAMP1). In the cranial dura mater, CLR and RAMP1 immunoreactivity (-ir) was found within arterial blood vessels, mononuclear cells, and Schwann cells, but not sensory axons. In the trigeminal ganglion, besides Schwann and satellite cells, CLR- and RAMP1-ir was found in subpopulations of CGRP-ir neurons where colocalization of CGRP- and RAMP1-ir was very rare ( approximately 0.6%). CLR- and RAMP1-ir was present on central, but not peripheral, axons. In the spinal trigeminal nucleus, CLR- and RAMP1-ir was localized to "glomerular structures," partly colocalized with CGRP-ir. However, CLR- and RAMP1-ir was lacking in central glia and neuronal cell bodies. We conclude that CGRP receptors are associated with structural targets of known CGRP effects (vasodilation, mast cell degranulation) and targets of unknown function (Schwann cells). In the spinal trigeminal nucleus, CGRP receptors are probably located on neuronal processes, including primary afferent endings, suggesting involvement in presynaptic regulation of nociceptive transmission. Thus, in the trigeminovascular system CGRP receptor localization suggests multiple targets for CGRP in the pathogenesis of primary headaches.

Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: Differences between peripheral and central CGRP receptor distribution

Recent research has shown that peripheral mechanisms of pain are much more complex than previously thought, and they differ for acutely injured normal tissues compared with chronic inflammation or neuropathic (nerve injury) pain. The purpose of the present review is to describe uses of dental injury models as experimental tools for understanding the normal functions of polymodal nociceptive nerves in healthy tissues, their neuroinflammatory interactions, and their roles in healing. A brief review of normal dental innervation and its interactions with healthy pulp tissue will be presented first, as a framework for understanding the changes that occur after injury. Then, the different types of dental injury that allow gradation of the extent of tissue damage will be described, along with the degree and duration of inflammation, the types of reactions in the trigeminal ganglion and brainstem, and the type of healing. The dental injury models have some unique features compared with neuroinflammation paradigms...

Dental Injury Models: Experimental Tools for Understanding Neuroinflammatory Interactions and Polymodal Nociceptor Functions

The parietal dura mater encephali of the rat was shown by immunohistochemistry to be densely innervated by calcitonin gene related peptide (CGRP) immunoreactive nerve fibers spreading around the me...

Calcitonin gene related peptide released from dural nerve fibers mediates increase of meningeal blood flow in the rat

Silent and active nociceptors: structure, functions and clinical implications.

SUMMARY

Two different techniques for three-dimensional reconstructions of nerve fibres or other extended fine tissue structures were developed to study the afferent innervation of the cat's knee-joint capsule.



The re-embedding technique starts with series of semithin sections for light microscopic reconstructions. In a second step, selected semithin sections can be re-embedded for ultramicrotomy to examine ultrastructural details. This method offers the possibility to investigate fine structures over a distance of several hundred micrometres without any loss of ultrastructural information.



The serial section-ESI technique is based on the electron spectroscopic imaging of semithin sections. Small tissue blocks are cut into series of either semithin or alternate semi- and ultrathin sections which can be directly used for a complete ultrastructural investigation.



Finally, true-to-scale three-dimensional reconstructions are performed by graphical techniques or computer-aided methods.

Serial sectioning, electron microscopy, and three‐dimensional reconstruction of fine nerve fibres and other extended objects

In recent years the normal and artificially inflamed knee joint of the cat has become an important model for neurophysiological studies on arthritic pain. The noxious stimuli causing pain are presumably perceived via “free nerve endings”, i.e., non-corpuscular endings of thinly myelinated fine afferent nerve fibers (group III or A ∂-fibers) and of non-myelinated fine afferent group IV or C-fibers (Schaible and Schmidt, 1983a, b, 1985; Grigg et al., 1986). But in comparison with neurophysiological knowledge, little is known about the morphological characteristics of articular “free nerve endings”. This is why we have studied the ultrastructure of “free nerve endings” and fine afferent nerve fibers in the normal knee joint capsule of the cat by serial sectioning and with three-dimensional reconstruction of nerve fibers for up to 300 µm length.

Karl Meßlinger

Papers

Calcitonin gene related peptide released from dural nerve fibers mediates increase of meningeal blood flow in the rat

Silent and active nociceptors: structure, functions and clinical implications.

Serial sectioning, electron microscopy, and three‐dimensional reconstruction of fine nerve fibres and other extended objects

The Sensory Terminal Tree of “Free Nerve Endings” in the Articular Capsule of the Knee

Nociception in normal and arthritic joints: structural and functional aspects