Physiological Society Symposium Nociceptors as Homeostatic Afferents: Central Processing

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1 Physiological Society Symposium Nociceptors as Homeostatic Afferents: Central Processing Distinct central representations of inescapable and escapable pain: observations and speculation Kevin A. Keay * and Richard Bandler * * Department of Anatomy and Histology and Pain Management and Research Centre, Royal North Shore Hospital, The University of Sydney, New South Wales 2006, Australia It is well established clinically that the affective response to pain of deep origin (muscles, joints and viscera) is distinct from that evoked by cutaneous pain. Cutaneous pain triggers a fight flight reaction (active emotional coping), whereas deep pain evokes a reaction of quiescence, decreased vigilance and vasodepression (passive emotional coping). These observations led to suggestions of distinct central representations for deep versus cutaneous pain. Indeed, studies using immediate early gene (c-fos) expression revealed selective activation of ventrolateral versus lateral columns of the midbrain periaqueductal grey region (PAG) by persistent pain of deep origin versus intermittent cutaneous pain. Ventrolateral versus lateral PAG activation had been found earlier to evoke passive versus active emotional coping. However, not all cutaneous pain triggers active coping. Persistent cutaneous pain (e.g. burns) instead, usually evokes passive coping. This raised the question of whether the behavioural significance of pain (i.e. its escapability versus inescapability), rather than its tissue origin, is represented in supraspinal regions such as the PAG. Subsequent study revealed that a persistent (inescapable) noxious cutaneous manipulation (clip of the neck) evoked both selective ventrolateral PAG Fos expression and passive emotional coping. Such data suggest that pain representation in the PAG reflects a quality akin to behavioural significance, rather than tissue origin. In contrast, in the spinal cord predominantly superficial dorsal horn Fos expression was seen after either persistent or intermittent noxious cutaneous stimuli, leaving the question of the pathway(s) via which persistent (inescapable) cutaneous pain activates the vlpag unanswered. One experimental approach to this question is suggested. Experimental Physiology (2002) 87.2, Different types of pain and their behavioural significance Nearly 60 years ago Sir Thomas Lewis (1942) called attention to the fact that the affective response evoked by pain of deep origin (arising from muscles, joints and viscera) was quite different from that evoked by cutaneous pain. Cutaneous pain, he noted, triggered a response characterised by fight or flight, increased vigilance, hyperreactivity, hypertension and tachycardia (i.e. active emotional coping/engagement with the environment). In contrast, deep pain usually triggered a reaction characterised by quiescence, decreased vigilance, decreased reactivity, hypotension, sweating, nausea and often bradycardia and hypotension (i.e. passive emotional coping/disengagement from the environment). So different were these affective responses that Lewis concluded that the central representations of deep versus cutaneous pain must be different (Lewis, 1942). Lewis wrote: The differences in the qualities of skin pain and of deep pain is so clear and each belongs so exclusively to the corresponding structures that it would seem unsafe to class both together under the one unqualified term pain. It has been the usage; but these two sensations have not been shown to possess the common properties which the use of a single term would imply. If we are right in believing that the system of fibres subserving cutaneous pain passes to an appropriate and exclusive part of the sensorium which determines this particular sensation, we are brought to consider whether or not fibres subserving pain derived more deeply connects to a distinct part of the sensorium... we should bear in mind the possible serious Article solicited after the Physiological Society Symposium held at the University of Bristol in September Publication of The Physiological Society Corresponding author: periaq@anatomy.usyd.edu.au 2355

2 276 K. A. Keay and R. Bandler Exp. Physiol fallacy of regarding both types as represented in a common centre. (our italics) Recently, this concept of distinct central representations for deep versus cutaneous pain has been confirmed for at least one brain region, the midbrain periaqueductal grey (PAG). Using the expression of the immediate early gene, c-fos, as a marker of neuronal activation, we and others reported that noxious stimulation of a range of deep somatic and visceral structures evoked a selective increase in Fos expression in the ventrolateral PAG column (vlpag), whereas, noxious cutaneous stimulation evoked Fos expression predominantly in the lateral PAG column (lpag) (Keay & Bandler, 1993, 1998; Keay et al. 1994, 2000a,b; Tassorelli & Joseph, 1995; Clement et al. 1996). We found earlier that microinjection of excitatory amino acids (EAA) in the vlpag of freely moving animals evoked a response of quiescence, decreased vigilance, decreased reactivity, hypotension and bradycardia, remarkably similar to the passive coping reaction evoked by deep pain; Figure 1 Top row: left-hand side, a schematic, representative section of the upper cervical spinal cord (C1 2) illustrating the location of Fos-like immunoreactive (IR) neurones (filled dots) in a single 40 mm section following radiant heat applied to the skin of the neck (Intermittent Cutaneous). The laminar boundaries indicate: superficial dorsal horn (laminae I III), deep dorsal horn and intermediate grey (laminae IV VII), ventral horn (laminae VII and IX) and lamina X; right-hand side, schematic representative sections through a 2.0 mm rostrocaudal extent of the PAG showing the locations of Fos-like IR neurones (filled dots) on one side of a 40 mm section, following the same manipulation. Similar patterns of Fos expression were observed bilaterally in the PAG. The shaded region shows the extent of the lateral PAG column. The numbers at the bottom of the panel indicate the rostrocaudal level of each section, in millimetres, caudal to bregma. Middle row: Fos-immunoreactive neurones in the upper cervical spinal cord (UCC) and PAG following the application of a clip to the skin of the neck (Persistent Cutaneous). Bottom row: UCC and PAG Fos expression following an injection of formalin into the deep neck muscles (Deep Somatic). The shaded region in these rows shows the extent of the ventrolateral PAG column.

3 Exp. Physiol Central pathways of inescapable and escapable pain 277 in contrast activation of the lpag evoked an active coping response (fight flight, increased vigilance, hyper-reactivity, hypertension and tachycardia) seemingly identical to that triggered by cutaneous pain (Bandler & Keay, 1996; Bandler, et al. 2000a,b). Thus, distinct PAG columns appear to play the different roles in mediating affective responses to deep and cutaneous pain that were first envisaged by Lewis (1942). However, not all noxious cutaneous stimuli trigger active coping. Clinically, if cutaneous pain persists (e.g. burns, including even moderate sunburn) a passive coping response is often provoked. Similarly, in the rat, a persistent noxious cutaneous stimulus (e.g. clip of the skin of the neck) has been found to evoke a passive emotional coping response (Fleischmann & Urca, 1988a,b,c, 1989, 1993). Such observations raise an interesting question. Is it the tissue origin (cutaneous versus deep) of the pain or its behavioural significance (escapability versus inescapability) that is represented in the PAG? Or, to put it in a slightly different context, if, as Wall (1979) suggested, a noxious event signals first and foremost the necessity to respond, it follows that the behavioural significance of the noxious event (its escapability or inescapability) must be represented, first and foremost, within the central nervous system. In this brief review we will: (i) present the results of an initial study that indicate that something akin to the behavioural significance of noxious events is represented within the PAG; (ii) consider briefly an experimental approach to the question of how persistence or inescapability could come to be represented within the vlpag. PAG: encoding of behavioural significance Figure 1 illustrates, for the rat, the patterns of Fos expression within the PAG following two noxious cutaneous, and one deep noxious manipulation (for details see Keay & Bandler, 1993; Keay, et al. 2001; the experimental protocols were approved by The University of Sydney Ethics Committee and conformed to Australian NHMRC guidelines for the use of animals in research). The protocols were as follows. (i) Intermittent Cutaneous: intermittent radiant heat (infra-red source, 5 min on, 5 min off) to the skin of the neck, raising surface temperature to 47 C. (ii) Persistent Cutaneous: an alligator clip applied to the skin of the nape of the neck. Figure 2 Upper row: schematic, representative sections of the upper cervical spinal cord (C1 2) (left-hand side) and segments of the lumbosacral spinal cord (right-hand side), illustrating the location of Fos-like IR neurones (filled dots) in five sections (40 mm thick) following an intramuscular injection of carrageenan into the gastrocnemius muscle. Lower row: similar schematic sections of the upper cervical spinal cord (C1 2) (left-hand side) and the lumbosacral spinal cord (right-hand side), illustrating the location of double labelled (i.e. retrogradely labelled from the vlpag and Fos-like IR) neurones in 10 sections (40 mm thick) following a similar intramuscular injection of carrageenan into the gastrocnemius muscle.

4 278 K. A. Keay and R. Bandler Exp. Physiol (iii) Deep Somatic: bilateral injection (0.05 ml) of 5 % formalin into deep dorsal neck muscles. It can be seen that predominantly lpag Fos expression was evoked by the intermittent noxious cutaneous manipulation (i.e. radiant heat). In contrast, both the persistent noxious cutaneous manipulation (i.e. the clip) and the noxious deep somatic manipulation (I.M. injection of formalin) evoked a selective and significant increase in Fos expression in the vlpag. Consistent with the data for Fos expression, in behavioural experiments (an 8 min social interaction test in a neutral test cage with a partner) there was a significant increase in the duration of quiescent behaviour (i.e. passive coping) in rats subjected to either the noxious deep somatic or the persistent noxious cutaneous manipulations (deep somatic pain, ± 43.1 s; persistent cutaneous pain, ± 31.5 s versus control, 93.3 ± 35.4 s) (for details see Keay et al. 2001). Spinal cord: encoding of tissue origin and behavioural significance It can be seen at the level of primary afferent termination in the upper cervical cord (Fig. 1) that noxious cutaneous manipulations, both intermittent (radiant heat) and persistent (clip), activated neurones primarily in the superficial dorsal horn (SDH). In contrast, the Fos distribution following the noxious deep somatic manipulation (I.M. injection of formalin) included substantial numbers of labelled neurones in the deep dorsal horn and medial ventral horn/lamina X, in addition to the SDH. There was activation also of neurones within the white matter adjacent to the dorsal horn (i.e. lateral spinal nucleus) for each of the manipulations (Fig. 1). The predominantly SDH activation by both the inescapable (persistent) and escapable (intermittent) noxious cutaneous stimuli raises the question of how inescapability or escapability comes to be encoded at higher levels of the neuraxis. One method of approaching this question is to identify the spinal neurones that project to a specific PAG column and are activated by an escapable or inescapable noxious stimulus. Although such studies have yet to be carried out for the vlpag and a persistent noxious cutaneous manipulation, such data are available for several noxious deep somatic and noxious visceral manipulations (Clement et al. 2000). Figure 2 provides an example from one set of experiments in which rats previously injected with a retrograde tracer (cholera toxin subunit B) in the vlpag were subjected, 3 5 days later, to a noxious deep somatic manipulation (bilateral injection into gastrocnemius/ soleus muscle of type IV carrageenan (2 %, 0.05 ml)). It can be seen (Fig. 2, lower diagram) that the distribution of double labelled (Fos + retrograde label) neurones was restricted almost exclusively to the lateral spinal nucleus (LSN), at both lumbosacral (level of primary afferent termination) and upper cervical (UCC) spinal cord levels. This is a remarkable finding, given that single labelled (Fos-positive) LSN neurones represent fewer than 10 % of the total numbers of single, Fos-labelled neurones at both lumbosacral and UCC levels (Fig. 2, upper diagram). Such data raise the possibility that afferent drive of LSN origin is in large part responsible for the deep noxious activation of the vlpag. Although the characteristics of vlpagprojecting LSN neurones have yet to be studied with single cell electrophysiological techniques, the Fos-retrograde data indicate that such neurones may respond well to deep noxious stimuli. Findings from the few electrophysiological studies that have attempted to record from LSN neurones indicate that it is quite difficult to activate these neurones with brief noxious cutaneous stimuli (e.g. Giesler et al. 1979a,b; Menetrey et al. 1980, 1989; Leah, et al. 1988). It would be interesting to determine whether LSN neurones respond better to persistent or prolonged noxious stimuli of cutaneous, as well as deep origin. To summarise, the data presented suggest that patterns of activation in different parts of the neuraxis reflect different noxious stimulus qualities. In the UCC the pattern of activation reflects primarily the tissue origin of the pain, that is, the distinct spinal distributions of primary afferents arising from skin rather than muscle. However, even though persistent and intermittent noxious cutaneous manipulations are characterised predominantly by SDH Fos expression, the data from experiments using a deep noxious stimulus (see Fig. 2) suggest that the small numbers of activated LSN neurones may be responsible for the selective activation of the vlpag by the persistent (inescapable clip) noxious cutaneous stimulus. For the PAG the pattern of neural activation clearly reflects a quality akin to the behavioural significance (escapability versus inescapability) of the noxious event. Recent studies by Lumb and colleagues indicate that behavioural significance may be similarly represented in regions of the hypothalamus which project specifically into dorsolateral/ lateral or ventrolateral PAG columns (see symposium paper by Lumb in this issue). Whether behavioural significance is similarly represented in other supraspinal regions remains to be studied. BANDLER, R. & KEAY, K. A. (1996). Columnar organization in the midbrain periaqueductal gray and the integration of emotional expression. Progress in Brain Research 107, BANDLER, R., KEAY, K. A., FLOYD, N. & PRICE, J. (2000a). Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Research Bulletin 53, BANDLER, R., PRICE, J. L. & KEAY, K. A. (2000b). Brain mediation of active and passive emotional coping. Progress in Brain Research 122, CLEMENT, C. I., KEAY, K. A., OWLER, B. K. & BANDLER, R. (1996). Common patterns of increased and decreased Fos expression in midbrain and pons evoked by noxious deep somatic and noxious visceral manipulations in the rat. Journal of Comparative Neurology 366, CLEMENT, C. I., KEAY, K. A., PODZBENKO, K., GORDON, B. D. & BANDLER, R. (2000). Spinal sources of noxious visceral and noxious deep somatic afferent drive onto ventrolateral periaqueductal gray of the rat. Journal of Comparative Neurology 425,

5 Exp. Physiol Central pathways of inescapable and escapable pain 279 FLEISCHMANN, A. & URCA, G. (1988a). Clip induced analgesia and immobility in the mouse: activation by different sensory modalities. Physiology and Behavior 44, FLEISCHMANN, A. & URCA, G. (1988b). Clip-induced analgesia and immobility in the mouse: pharmacological characterization. Neuropharmacology 27, FLEISCHMANN, A. & URCA, G. (1988c). Different endogenous analgesia systems are activated by noxious stimulation of different body regions. Brain Research 455, FLEISCHMANN, A. & URCA, G. (1989). Clip-induced analgesia: noxious neck pinch suppresses spinal and mesencephalic neural responses to noxious peripheral stimulation. Physiology and Behavior 46, FLEISCHMANN, A. & URCA, G. (1993). Tail-pinch induced analgesia and immobility: altered responses to noxious tail-pinch by prior pinch of the neck. Brain Research 601, GIESLER, G. J. JR, MENETREY, D. & BASBAUM, A. I. (1979a). Differential origins of spinothalamic tract projections to medial and lateral thalamus in the rat. Journal of Comparative Neurology 184, GIESLER, G. J. JR, URCA, G., CANNON, J. T. & LIEBESKIND, J. C. (1979b). Response properties of neurons of the lateral cervical nucleus in the rat. Journal of Comparative Neurology 186, KEAY, K. A. & BANDLER, R. (1993). Deep and superficial noxious stimulation increases Fos-like immunoreactivity in different regions of the midbrain periaqueductal gray of the rat. Neuroscience Letters 154, KEAY, K. A. & BANDLER, R. (1998). Vascular head pain selectively activates ventrolateral periaqueductal gray in the cat. Neuroscience Letters 245, KEAY, K. A., CLEMENT, C. I. & BANDLER, R. (2000a). The neuroanatomy of cardiac nociceptive pathways: Differential representations of superficial and deep pain. In The Nervous System and the Heart, ed. TER-HORST, G., pp Humana Press, NJ, USA. KEAY, K. A., CLEMENT, C. I., DEPAULIS, A. & BANDLER, R. (2001). Different representations of inescapable noxious stimuli in the periaqueductal grey and upper cervical spinal cord of freely moving rats. Neuroscience Letters 313, KEAY, K. A., CLEMENT, C. I., OWLER, B. K., DEPAULIS, A. & BANDLER, R. (1994). Convergence of deep somatic and visceral nociceptive information onto a discrete ventrolateral midbrain periaqueductal gray region. Neuroscience 61, KEAY, K. A., LI, Q. F. & BANDLER, R. (2000b). Muscle pain activates a direct projection from ventrolateral periaqueductal gray to rostral ventrolateral medulla in rats. Neuroscience Letters 290, LEAH, J., MENETREY, D. & DE POMMERY, J. (1988). Neuropeptides in long ascending spinal tract cells in the rat: evidence for parallel processing of ascending information. Neuroscience 24, LEWIS, T. (1942). Pain. McMillan, London. MENETREY, D., CHAOUCH, A. & BESSON, J. M. (1980). Location and properties of dorsal horn neurons at origin of spinoreticular tract in lumbar enlargement of the rat. Journal of Neurophysiology 44, MENETREY, D., GANNON, A., LEVINE, J. D. & BASBAUM, A. I. (1989). Expression of c-fos protein in interneurons and projection neurons of the rat spinal cord in response to noxious somatic, articular, and visceral stimulation. Journal of Comparative Neurology 285, TASSORELLI, C. & JOSEPH, S. A. (1995). Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Research 682, WALL, P. D. (1979). On the relation of injury to pain. Pain 6, Acknowledgements The authors acknowledge the financial support of the NHMRC (Australia) for their work reviewed in this paper.

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