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

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The induction of pain: an integrative review

Interneuronal relay in spinal pathways from proprioceptors

Neuropathic pain is defined as ‘pain initiated or caused by a primary lesion or dysfunction in the nervous system’. 94 The spectrum of neuropathic pain covers a variety of disease states (Table 1) and presents in the clinic with a variety of symptoms. 145 Neuropathic pain is often reported as having a lancinating or continuous burning character and is often associated with the appearance of abnormal sensory signs, such as allodynia (pain as a result of a stimulus which does not normally provoke pain) or hyperalgesia (an increased response to a stimulus which is normally painful) (Figure 1). The sensory phenomena can be further characterized into static or dynamic sub-types. The mechanistic implication of allodynia is that elements of the sensory nervous system, which normally signal innocuous sensation have begun to encode painful stimuli, whilst in hyperalgesia the structures that sub-serve nociception have become hyperexcitable. Neuropathic pain is an area of largely unmet therapeutic need. The current pharmacological mainstays of clinical management are tricyclic anti-depressants and certain anticonvulsants, 92 119 but these only achieve clinically significant (greater than 50%) pain relief in less than 50% of patients and are associated with sub-optimal side effect profiles. Opioids are generally considered to be less effective in neuropathic pain than in inflammatory pain, with the dose response curve of opioids in neuropathic pain shifted to the right of that for inflammatory pain, although the extent of this difference is controversial. 112 The majority of research into neuropathic pain mechanisms has concentrated on changes in the peripheral nerve or spinal cord after peripheral nerve injury and, therefore, most available evidence relates to changes in these parts of the nervous system and the review will, therefore, focus on these aspects. Nevertheless, it is important to recognize that alterations in the brain have also been demonstrated following peripheral nerve injury, but much less is known about the significance of these changes. For example, phantom limb pain has been shown to be associated with reorganization of the cortex of humans. 43 The degree of cortical re-organization, as determined by BTi neuromagnetic imaging, was linked in a linear fashion to the intensity of pain, with an increase in re-organization being associated with greater pain intensity. 43 A more recent study indicated that cortical re-organization was evident only in patients with phantom limb pain, and not in patients with non-painful phantom limb phenomena or congenital absence of the limb. 44

Mechanisms of neuropathic pain

Nociception from skeletal muscle in relation to clinical muscle pain.

We studied the spinal projections of the medial and posterior articular nerves (MAN and PAN) of the knee joint in the cat with the aid of the transganglionic transport of horseradish peroxidase. The afferent fibers of the MAN entered the spinal cord via the lumbar dorsal roots L5 and L6 and those of the PAN entered via the dorsal roots L6 and L7. Within the dorsal root ganglia, most labeled neurons had small to medium diameters. A relatively higher number of medium-size cell bodies were labeled from the PAN than from the MAN. In the spinal cord labeled MAN afferent fibers and terminations were most dense in the L5 and L6 segments, and those of the PAN were most dense in L6 and L7, that is, in the respective segments of entry. Labeled afferent fibers from both nerves projected rostrally at least as far as L1 and caudally as far as S2. Labeled fibers were found in Lissauer's tract as well as in the dorsal column immediately adjacent to the dorsal horn. In the spinal gray matter, both nerves had two main projection fields, one in the cap of the dorsal horn in lamina I, the other in the deep dorsal horn in laminae V-VI and the dorsal part of lamina VII. Both nerves, but particularly the PAN, projected to the medial portion of Clarke's column. No projection was found to laminae II, III, and IV of the dorsal horn or to the ventral horn. Since these findings parallel observations on hindlimb muscle afferent fibers, the present data support the existence of a common pattern for the central distribution of deep somatic afferent fibers.

The projection of the medial and posterior articular nerves of the cat's knee to the spinal cord.

The noncorpuscular endings ("free nerve endings") of thinly myelinated group III and nonmyelinated group IV afferent nerve fibers have been examined in the knee joint capsule of sympathectomized cats by transmission electron microscopy and three-dimensional reconstruction of series of semi- and ultrathin sections. The sensory ending is the most distal part of a group III or IV nerve fiber that consists only of the sensory axon and associated Schwann cells but lacks a myelin sheath and is not surrounded by perineurium. The sensory axon divides into several branches and forms a terminal tree. The branches run either as single fibers or within small Remak bundles in parallel to sensory axons of other endings; they spread along vessel walls and also extend into dense connective tissue. Each sensory axon consists of a series of spindle-shaped thick segments ("beads") connected by waist-like thin segments. Thus all axons of sensory endings have a string-of-beads appearance, which resembles that of efferent sympathetic nerve fibers. The beads of the sensory axon and the end bulb at its tip show the same ultrastructural features which are characteristic of receptive sites: an accumulation of mitochondria and glycogen particles and various vesicles in the axoplasm and "bare" areas of axolemma that are not covered by Schwann cell processes. Group III and group IV sensory endings differ in the length of their branches (up to 200 microM in group III vs. more than 300 microM in group IV), number of beads per 100 microM axon length (about seven vs. nine or ten), mean diameter of axons (0.9-1.5 microM vs. 0.3-0.6 microM), and the presence of a neurofilament core consisting of bundles of parallel microfilaments only in group III. In conclusion, we propose that the sensory part of noncorpuscular "free nerve endings" is formed by the entire terminal tree of group III or group IV nerve fibers and that the beads in the course of the sensory axon represent multiple receptive sites.

Ultrastructural three-dimensional reconstruction of group III and group IV sensory nerve endings ("free nerve endings") in the knee joint capsule of the cat: evidence for multiple receptive sites.

Bernd Heppelmann

Papers

The projection of the medial and posterior articular nerves of the cat's knee to the spinal cord.

Ultrastructural three-dimensional reconstruction of group III and group IV sensory nerve endings ("free nerve endings") in the knee joint capsule of the cat: evidence for multiple receptive sites.

Sensitisation of articular afferents in normal and inflamed knee joints by substance P in the rat

Substance P- and calcitonin gene-related peptide immunoreactivity in primary afferent neurons of the cat's knee joint.

Nerve growth factor regulates the expression of bradykinin binding sites on adult sensory neurons via the neurotrophin receptor p75