Pain and stress in a systems perspective: reciprocal neural, endocrine, and immune interactions

Abstract

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.

Figure 1. The Hypothalamo-Pituitary-Adrenocortical Axis Stress Response

Nociceptive signaling acts directly upon the hypothalamic PVN, but also upon the PAG, the LC, the cortico-amygdalar circuit, and also triggers release of pro-inflammatory cytokines from various immune cells and the adrenal medulla. All of these activate the PVN, which normally responds to diurnal rhythm and associated circulating cortisol levels. Stressor-induced activation of the PVN releases CRH from the median eminence into portal circulation. This stimulates the anterior pituitary and causes the release of ACTH into systemic circulation. ACTH provokes cortisol release at the adrenal cortex. Cortisol has widespread effects on a wide array of target organs. Because this is a negative feedback system, cortisol provides feedback to both the PVN and the anterior pituitary, thus controlling axis activity. PVN: periventricular nucleus of hypothalamus; PAG: periaqueductal gray; ACTH: adrenocorticotropic hormone, or corticotropin; CRH; corticotropin-releasing hormone.

Figure 2. Connectivity

Nervous, endocrine and immune subsystems communicate dynamically using the language of common chemical substances, as indicated in the center of the figure. The major language elements are peptides, hormones, neurotransmitters, endocannabinoids and cytokines. These substances are pleiotropic in that they exert different effects depending upon context (e.g., phase and location). Circulation, diffusion and migration are some of the processes of information transmission. Systemic circulation and autonomic nervous system activity are other vehicles of information transmission. Because the nervous, endocrine and immune systems have constant reciprocal communication, they tend to react to a stressor in a highly orchestrated manner, as a single unit.

Figure 3. Stressors and the Chronic Pain Patient

A typical chronic pain patient has medical problems related to one or more historic events. These problems limit vocational options and normal social interactions, with resulting financial problems, social isolation and family distress. These processes comprise the explicit stressor constellation. Past history and memories of the patient, together with negative thinking, comprise the implicit stressor constellation. Catastrophic thinking is the tendency to frame every problem with a worst-case scenario. Patients tend to engage in it because of anxiety about their explicit problems. The negative thinking becomes its own stressor. Moreover, it makes relationships with people offering social and medical support difficult. Often, social problems and a sense of being a victim generate anger, which complicates vocational and family relationships and exacerbates the explicit stressor constellation. Measures of social conflict processes characterize patient social interactions as the interactions of a subsystem within the larger system that surrounds it.