Review of overlap between thermoregulation and pain modulation in fibromyalgia

Abstract

Fibromyalgia (FM) syndrome is characterized by widespread pain that is exacerbated by cold and stress but relieved by warmth. We review the points along thermal and pain pathways where temperature may influence pain. We also present evidence addressing the possibility that brown adipose tissue activity is linked to the pain of FM given that cold initiates thermogenesis in brown adipose tissue through adrenergic activity, whereas warmth suspends thermogenesis. Although females have a higher incidence of FM and more resting thermogenesis, they are less able to recruit brown adipose tissue in response to chronic stress than males. In addition, conditions that are frequently comorbid with FM compromise brown adipose activity making it less responsive to sympathetic stimulation. This results in lower body temperatures, lower metabolic rates, and lower circulating cortisol/corticosterone in response to stress--characteristics of FM. In the periphery, sympathetic nerves to brown adipose also project to surrounding tissues, including tender points characterizing FM. As a result, the musculoskeletal hyperalgesia associated with conditions such as FM may result from referred pain in the adjacent muscle and skin.

Figure 1

Comparison between the location of tender points and BAT depots in humans. Panel A shows the location of the 18 tender points, located symmetrically, used to characterize the pain of fibromyalgia (http://www.niams.nih.gov/Health_Info/Fibromyalgia/default.asp). Panel B shows the PET scan of an individual taken during exposure to cold (left panel of figure 1B), when BAT tissue is active and visible, compared to when exposed to thermoneutral conditions (right panel of figure 1B) (from Lichtenbelt, Vanhommerig, Smulders, Drossaerts, Kemerink, Bouvy, Schrauwen and Teule).

Figure 2

Activation of brown adipose tissue may support referred pain in a fashion similar to that during attacks of angina or during the processing of other internal signals (interoception). Schematic diagram of the possible circuitry linking brown adipose tissue to surrounding muscle and skin via collateral projections of sympathetic and primary afferent C-fibers. Visceral afferent information also projects upward in the neuraxis to the nucleus tractus solitarius (NTS) and paraventricular hypothalamus (PVH). In turn, the NTS projects to the PVH, central nucleus of the amygdala, PB, and the bed nucleus of the stria terminalis (BSST). The PVH has reciprocal connections with periaqueducal grey (PAG) and amygdala. The latter directly and indirectly modulates paralimbic cortices such as the ventromedial prefrontal cortex (VMPFC), anterior cingulate cortex (ACC) and insula thereby processing the emotional responses to pain and temperature proposed to be dysfunctional in fibromyalgia. In turn, the VMPFC has efferent modulatory projections to the PAG, hypothalamus (Hyp), and amygdala. Descending inhibitory control is exerted by the periaqueductal gray (PAG) and locus coeruleus (LC) via the rostroventral medulla (RVM) where ‘on’ and ‘off’ cells differentially modulate nociceptive signals entering at the spinal cord level.