This paper advances a psychophysiological systems view of pain in which physical injury, or wounding, generates a complex stress response that extends beyond the nervous system and contributes to the experience of pain. Through a common chemical language comprising neurotransmitters, peptides, endocannabinoids, cytokines and hormones, an ensemble of interdependent nervous, endocrine, and immune processes operates in concert to cope with the injury. These processes act as a single agent and comprise a supersystem. Acute pain in its multiple dimensions, and the related symptoms that commonly occur with it, are products of the supersystem. Chronic pain can develop as a result of unusual stress. Social stressors can compound the stress resulting from a wound or act alone to dysregulate the supersystem. When the supersystem suffers dysregulation, health, function and sense of well-being suffer. Some chronic pain conditions are the product of supersystem dysregulation. Individuals vary and are vulnerable to dysregulation and dysfunction in particular organ systems due to the unique interactions of genetic, epigenetic and environmental factors, as well as the past experiences that characterize each person.Perspective-Acute tissue injury activates an ensemble of interdependent nervous, endocrine and immune processes that operate in concert and comprise a supersystem. Some chronic pain conditions result from supersystem dysregulation. Individuals vary and are vulnerable to dysregulation due to the unique interactions of genetic, epigenetic and environmental factors, and past experiences that characterize each person. This perspective can potentially assist clinicians in assessing and managing chronic pain patients.

SUMMARY1. In the cat anaesthetized with sodium pentobarbitone, electrical activity was recorded from single unmyelinated sensory fibres innervating the cornea.2. Based on their response to mechanical (calibrated aesthesiometer), chemical (10 mm acetic acid or 616 mm NaCl) and thermal (cooling from 35 to 5°C; heating to 51°C) stimuli, corneal unmyelinated fibres were classified as polymodal (71 %) or 'cold' nociceptors (29 %).3. Polymodal units responded to mechanical indentation of the cornea and developed fatigue after repeated stimulation. They were excited by temperatures over 37°C and exhibited sensitization to repeated heating.4. Corneal polymodal units were also activated by topical application of 10 mM acetic acid and hypertonic NaCl (616 mM). Capsaicin (0 33 mM) elicited a discharge of impulses that was followed by inactivation to mechanical, chemical and thermal stimuli.5. 'Cold' nociceptors had small receptive fields, preferentially located at the periphery of the cornea. They were excited by small temperature decreases of the corneal surface in a range between 30 and 8°C, but were not responsive to noxious heat.6. 'Cold' nociceptors encoded temperature changes between 35 and 23 'C. The discharge was proportional to the velocity of the temperature drop; sustained temperatures were not signalled by changes in static frequency values. 'Cold' nociceptive fibres responded to hypertonic NaCl (616 mM) and weakly to 10 mM acetic acid. Capsaicin (0 33 mM) first excited and then inactivated 'cold' nociceptors.7. Thermoreceptive fibres were found in the episclera. They fired in bursts and responded to small temperature decreases, but were insensitive to irritant chemicals and capsaicin.

The cutaneous mechanoreceptors of the cat can be assigned to one of 11 groups by using physiologic tests performed with hand-held stimulators. The method of classification is described, and the validity and utility of this classification scheme are discussed.

Psychophysical experiments were done to test the possibility that a single receptor population signals both itch and pain by generating different patterns of activity for each type of stimulus. Electrical stimulation of hairy skin evoked pruritus in 92% of the subjects tested, and for the majority the pruritus elicited by electrical stimulation felt the same as that provoked by cowhage. The intensity of pruritus increased with the frequency of stimulation with no change in the quality of the sensation from itch to pain. Electrical stimulation of human skin with response patterns obtained from individual cat polymodal nociceptive neurons to pain- and itch-producing stimuli caused no differences in the quality of the evoked pruritic sensations. These results do not support the idea that the same population of primary sensory neurons can produce both itch and pain by changing their pattern of discharge.

Immunoreactivity to serotonin was observed in Merkel cells as well as the afferent type I nerves terminating upon them in touch domes excised from the belly skin of rats. Type I nerves were strongly immunoreactive and could be traced through the dermis of the domal papilla. Merkel cell immunoreactivity was sometimes seen in the entire cell, but was often localized in the Merkel cell cytoplasm adjacent to nerve terminals and may have been in the terminals themselves. Domes were fixed by immersion in 4% paraformaldehyde-lysine-sodium-m-periodate (PLP) fixative at 4 degrees C for 2.5-3 hours and cryoprotected in 30% sucrose overnight. Sections were processed with the avidin-biotin complex peroxidase (ABC), peroxidase-antiperoxidase (PAP), and indirect immunofluorescence techniques with rabbit antiserum generated against serotonin.