When Stress Hurts: Neurochemistry Cognates

In this third post in the series on the close association between psychological stress and psychogenic pain, we take a look at neurochemical substances that are involved in the process of psychogenic pain generation and reaction to psychological stress.

The Neurochemistry of Pain: Substance P

aaGiotto_DeposizioneSubstance P, discovered in the 1950s, is the quintessential pain neurochemical, which is activated in response to physiological pain as well as to psychological stress (DeVane, 2001). It is a prototypic neuropeptide of the tachykinin family that has been linked to the production of over 50 neuroactive chemical substances (Brain & Cox, 2006). Its best documented role is as the modulator of signals to nociceptive neurons that communicate the intensity of noxious or adverse stimuli, not only those caused by pain but also those produced by psychological stress (DeVane, 2001; Shaikh, Steinberg, & Siegel, 1993). Substance P receptors are found throughout the CNS but especially in the substantia gelatinosa of the dorsal horn, which is the first point of arrival of afferent pain signals to primary nociceptive fibers.

It is not coincidental that Substance P is also present in the limbic system of the CNS, in the hypothalamus and in the amygdala, all structures that are closely associated with the perception and processing of emotions (Bannon et al., 1983; Culman & Unger, 1995; DeVane, 2001; Stahl, 1999).

Some purely psychological and psychogenic reactions of the organism also see the involvement of substance P, such as the vomiting reflex, anger and defensive behaviors (Krase, Koch, & Schnitzler, 1994), changes in cardiovascular tone (Black & Garbutt, 2002), stimulation of salivary secretions, and other physiological responses that are associated with the general adaptation of the body (Selye & Fortier, 1950) to stressful stimulation.

Kohlmann and colleagues (1997) reported the discovery of substance P in blood pressure regulation in individuals with essential hypertension, a condition that has been related to maladaptive responses to stress (Palomo et al., 2003) and has been shown to respond to psychotherapeutic interventions (Amigo, Buceta, Becona, & Bueno, 1991). Other evidence of the concurrent role of substance P in signaling pain and in the stress reaction comes from animal studies that show an array of defensive behavioral and cardiovascular changes in animals subjected to stressful stimulation (Krase et al., 1994), as well as the detection of substance P in the amygdala of laboratory animals upon neonatal separation (Kramer et al., 1998).

The Neurochemistry of Stress

The neuroendocrine response to a real or perceived stressor consists of the near simultaneous release by the sympathetic nervous system (SNS) of the catecholamines norepinephrine (NE) and epinephrine, the release by the hypothalamus of corticotrophin releasing hormone (CRH), the inhibition by the hypothalamus of gonadotropin releasing hormone (GnRH) and pituitary gonadotropins, the release by the pituitary gland of prolactin (PRL), and the release by the pancreas of glucagon (Sapolsky et al., 2000).

Upon release of NE into the synaptic cleft, approximately 10% of it enters the plasma, thus making plasma NE levels one of the most reliable measures of SNS activity and the magnitude of the body’s response to stressors. Peroutka (2004) has proposed that a migraine attack may be triggered by a significant decrease of NE due to the excessive or prolonged release of adenosine, dopamine and prostaglandin by the over-stimulated SNS. Since sympathetic activation is the primary component of the stress response, stress is thus unequivocally linked to the onset and maintenance of migraine headaches.

The Closest Association: Stress-Induced Analgesia

Livingstone_LionRThe body’s reactivity to real or perceived stressors provokes measurable changes in the autonomic nervous system (ANS) and in the structures controlled by the hypothalamic-pituitary-adrenal (HPA) axis. These changes include blood pressure elevation, pupil dilation, and secretion of cortisol. In the presence of a significant stressor, the stress response also includes a “stress induced analgesia,” or a decreased sensitivity to further pain (as writer-explorer David Livingstone so eloquently reported). This antinociceptive action of the ANS translates into an inverse relationship between blood pressure and pain sensitivity in animals and humans, and is designed to maintain the integrity of the body’s defense systems. Additionally, the release of CRF by the hypothalamus has known analgesic effects (Okifuji & Turk, 2002).

The ANS was recognized by Cannon (1914; Cannon, 1933) as the originator and enabler of the “fight or flight” response to stress. Stress-related releases of adrenaline stimulate the feedback provided by the afferent and efferent vagal fibers. Once again, these same fibers are involved in the activation of endogenous pain modulation centers (Bielefeldt, Christianson, & Davis, 2005). Pain and stress just seem to go together.

Previously in this series:


  • Psychological Stressors and the Sudden Appearance of Psychogenic Pain
  • Fibromyalgia, Severe Headaches and Other Stress-Related Misery
  • Medical and Non-Medical Treatments for Stress and Psychogenic Pain