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

Animal studies suggest that fear inhibits pain whereas anxiety enhances it; however it is unclear whether these effects generalize to humans. The present study examined the effects of experimentally induced fear and anxiety on radiant heat pain thresholds. Sixty male and female human subjects were randomly assigned to 1 of 3 emotion induction conditions: (1) fear, induced by exposure to three brief shocks; (2) anxiety, elicited by the threat of shock; (3) neutral, with no intervention. Pain thresholds were tested before and after emotion induction. Results suggest that findings from animal studies extend to humans: fear resulted in decreased pain reactivity, while anxiety led to increased reactivity. Pain rating data indicated that participants used consistent subjective criteria to indicate pain thresholds. Both subjective and physiological indicators (skin conductance level, heart rate) confirmed that the treatment conditions produced the targeted emotional states. These results support the view that emotional states modulate human pain reactivity.

Fear and anxiety: divergent effects on human pain thresholds

It is common clinical experience that anxiety about pain can exacerbate the pain sensation. Using event-related functional magnetic resonance imaging (FMRI), we compared activation responses to noxious thermal stimulation while perceived pain intensity was manipulated by changes in either physical intensity or induced anxiety. One visual signal, which reliably predicted noxious stimulation of moderate intensity, came to evoke low anxiety about the impending pain. Another visual signal was followed by the same, moderate-intensity stimulation on most of the trials, but occasionally by discriminably stronger noxious stimuli, and came to evoke higher anxiety. We found that the entorhinal cortex of the hippocampal formation responded differentially to identical noxious stimuli, dependent on whether the perceived pain intensity was enhanced by pain-relevant anxiety. During this emotional pain modulation, entorhinal responses predicted activity in closely connected, affective (perigenual cingulate), and intensity coding (mid-insula) areas. Our finding suggests that accurate preparatory information during medical and dental procedures alleviates pain by disengaging the hippocampus. It supports the proposal that during anxiety, the hippocampal formation amplifies aversive events to prime behavioral responses that are adaptive to the worst possible outcome.

/pdf/exacerbation-of-pain-by-anxiety-is-associated-with-activity-m9uof5q7jg.pdf

Exacerbation of Pain by Anxiety Is Associated with Activity in a Hippocampal Network

In this book Professor Holmes discusses some of the evidence relating to one of the most baffling problems yet recognized by biologists-the factors involved in the regulation of growth and form. A wide range of possible influences, from enzymes to cellular competition, is considered. Numerous experiments and theories are described, with or without bibliographic citation. There is a list of references for each chapter and an index. The subject from a scientific standpoint is an exceedingly difficult one, for the reason that very little indeed is understood regarding such phenomena as differentiation. It follows that the problem offers fine opportunities for intellectual jousting by mechanists and vitalists, that hypotheses and theories must often be the weapons of choice, and philosophy the armor. Professor Holmes gives us a good seat from which to watch the combats, explains clearly what is going on, and occasionally slips away to enter the lists himself. This stereoscopic atlas of anatomy was designed as an aid in teaching neuro-anatomy for beginning medical students and as a review for physicians taking Board examinations in Psychiatry and Neurology. Each plate consists of a pair of stereoscopic photographs and a labelled diagram of the important parts seen in the photograph. Perhaps in this day of scarcity of materials, particularly of human brains hardened for dissection, photographs of this kind conceivably can be used as a substitute. Successive stages of dissection are presented in such a fashion that, used in conjunction with the dissecting manual, a student should be able to identify most of the important components of the nervous system without much outside help. The area covered is limited to the gross features of the brain and brain stem and perhaps necessarily does not deal with any of the microscopic structure. So much more can be learned from the dissection of the actual brain that it is doubtful if this atlas would be useful except where brains are not available. A good deal of effort has been spent on the preparation of this atlas, with moderately successful results.

The Integrative Action of the Nervous System.

Experiences of social rejection, exclusion or loss are generally considered to be some of the most 'painful' experiences that we endure. Indeed, many of us go to great lengths to avoid situations that may engender these experiences (such as public speaking). Why is it that these negative social experiences have such a profound effect on our emotional well-being? Emerging evidence suggests that experiences of social pain — the painful feelings associated with social disconnection — rely on some of the same neurobiological substrates that underlie experiences of physical pain. Understanding the ways in which physical and social pain overlap may provide new insights into the surprising relationship between these two types of experiences.

http://www.dejongeakademie.nl/shared/resources/documents/eisenberger-2012-nature.pdf/at_download/file

The pain of social disconnection: examining the shared neural underpinnings of physical and social pain

Four experiments are reported that explore whether spinal neurons can support instrumental learning. During training, one group of spinal rats (master) received legshock whenever one hindlimb was extended. Another group (yoked) received legshock independent of leg position. Master, but not yoked, rats learned to maintain their leg in a flexed position, exhibiting progressively longer flexions as a function of training (Experiment 1). All subjects were then tested by applying controllable shock to the same leg (Experiment 2). Master rats reacquired the instrumental response more rapidly (positive transfer), whereas yoked rats failed to learn (a learned helplessness-like effect). Disrupting response-outcome contiguity by delaying the onset and offset of shock by 100 ms eliminated learning (Experiment 3). Experiment 4 showed that shock onset contributes more to learning than does shock offset.

Instrumental learning within the spinal cord: I. Behavioral properties.

Instrumental learning within the spinal cord. II. Evidence for central mediation.

Spinalized rats given shock whenever 1 hind leg is extended learn to maintain that leg in a flexed position, a simple form of instrumental learning. Rats given shock independent of leg position do not exhibit an increase in flexion duration. Experiment 1 showed that 6 min of intermittent legshock can produce this deficit. Intermittent tailshock undermines learning (Experiments 2-3), and this effect lasts at least 2 days (Experiment 4). Exposure to continuous shock did not induce a deficit (Experiment 5) but did induce antinociception (Experiment 6). Intermittent shock did not induce antinociception (Experiment 6). Experiment 7 addressed an alternative interpretation of the results, and Experiment 8 showed that presenting a continuous tailshock while intermittent legshock is applied can prevent the deficit.

Instrumental learning within the spinal cord: IV. Induction and retention of the behavioral deficit observed after noncontingent shock.

Instrumental learning within the spinal cord: VI. The NMDA receptor antagonist, AP5, disrupts the acquisition and maintenance of an acquired flexion response.

Shocked rats (Rattus norvegicus) often exhibit longer tail withdrawal latencies to radiant heat, which suggests that exposure to shock reduces pain. But at the same time, rats appear hyperreactive to shock, suggesting than pain is enhanced. Experiment 1 replicated these findings and showed that when tail movement was monitored, shocked rats were less responsive to heat and hyperreactive to shock even when the same behavioral criteria were used. When latency to vocalize was measured, shocked rats appeared hyperreactive to both test stimuli (Experiments 2 and 3). Prior exposure to shock also enhanced the acquisition of conditioned fear in a different context (Experiment 4) and the speed with which rats learned a response to avoid a thermal stimulus (Experiment 5). The results suggest that exposure to shock enhances pain.

Robin L. Joynes

Papers

Instrumental learning within the spinal cord: I. Behavioral properties.

Instrumental learning within the spinal cord. II. Evidence for central mediation.

Instrumental learning within the spinal cord: IV. Induction and retention of the behavioral deficit observed after noncontingent shock.

Instrumental learning within the spinal cord: VI. The NMDA receptor antagonist, AP5, disrupts the acquisition and maintenance of an acquired flexion response.

Impact of shock on pain reactivity: II. Evidence for enhanced pain.