A possible neural basis for stress-induced hyperalgesia

Abstract

Intense stress and fear have long been known to give rise to a suppression of pain termed "stressinduced analgesia," mediated by brainstem pain-modulating circuitry, including pain-inhibiting neurons of the rostral ventromedial medulla. However, stress does not invariably suppress pain, and indeed, may exacerbate it. Although there is a growing support for the idea of "stress-induced hyperalgesia," the neurobiological basis for this effect remains almost entirely unknown. Using simultaneous single-cell recording and functional analysis, we show here that stimulation of the dorsomedial nucleus of the hypothalamus, known to be a critical component of central mechanisms mediating neuroendocrine, cardiovascular and thermogenic responses to mild or "emotional" stressors such as air puff, also triggers thermal hyperalgesia by recruiting pain-facilitating neurons, "ON-cells", in the rostral ventromedial medulla. Activity of identified RVM ON-cells, OFF-cells and NEUTRAL cells, nociceptive withdrawalthresholds, rectal temperature, and heart rate were recorded in lightly anesthetized rats. In addition to expected increases in body temperature and heart rate, disinhibition of the DMH induced a robust activation of ON-cells, suppression of OFF-cell firing and behavioral hyperalgesia. Blocking ONcell activation prevented hyperalgesia, but did not interfere with DMH-induced thermogenesis or tachycardia, pointing to differentiation of neural substrates for autonomic and nociceptive modulation within the RVM.These data demonstrate top-down activation of brainstem pain-facilitating neurons, and suggest a possible neural circuit for stress-induced hyperalgesia.

Physiological Basis for Inhibition of Morphine and Improgan Antinociception by CC12, a P450 Epoxygenase Inhibitor

“…The holding temperature obviates any concern that apparent effects on reflex latency could be attributed to changes in skin temperature. Previous work has shown that response latencies and neuronal response properties are stable for a period of several hours with this testing protocol (Edelmayer et al 2009;Heinricher et al 2004Heinricher et al , 2010Kincaid et al 2006;Martenson et al 2009). …”

Cervical Referral of Head Pain in Migraineurs: Effects on the Nociceptive Blink Reflex

“…50 While the exact mechanisms responsible for emotional modulation of pain are not fully understood, heightened anxiety appears to increase sensitivity to pain (hyperalgesia), [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] while moderate fear inhibits pain (hypoalgesia). 51,[69][70][71][72][73][74][75][76][77] This suggests that anticipation of an unpredictable, threatening intervention could result in enhanced pain, while hypoalgesia results from exposure to a predictable, threatening event (fear). 51 As we did not assess the participants' psychological state, we are unsure whether this changed over the course of the experiment.…”

Evaluation of different procedure involved in the Transcranial Direct Current Stimulation (tDCS) technique experimental application

“…An important point is that the animals did not present analgesia immediately after 20 minutes of restraint, showing that these animals were not able to respond with stress-induced analgesia (SIA) or 20 min of restraint is not enough to promote SIA. Unlike acute stress, which has been related to a reduction in pain sensitivity, probably mediated by brainstem pain modulation 42 , chronic stress exposure has been associated with decreased pain threshold. Indeed, chronic stress is associated with increased sensitivity to pain, producing hyperalgesia 19,22,43,44 , and allodynia 19,43 .…”

“…Under these conditions, we can also suggest that data found in our study may be related to an effect of stress on the opioid system. Another possibility is that the activation of stress-related circuitry in the hypothalamus activates pain-facilitating neurons in the rostral ventromedial medulla to produce hyperalgesia, suggesting possible changes in brain activity 42 . It has also been postulated that the opioid system, which is an important modulator of the descending pathway of pain, could be implicated in the pain suppression mechanism 48 .…”