Social stress exacerbates the aversion to painful experiences in rats exposed to chronic pain: The role of the locus coeruleus

Abstract

a b s t r a c tStressful experiences seem to negatively influence pain perception through as yet unknown mechanisms. As the noradrenergic locus coeruleus (LC) nucleus coordinates many components of the stress response, as well as nociceptive transmission, we evaluated whether the sensory and affective dimension of chronic neuropathic pain worsens in situations of stress due to adaptive changes of LC neurons. Accordingly, male rats were socially isolated for 5 weeks, and in the last 2 weeks, neuropathic pain was induced by chronic constriction injury. In this situation of stress, chronic pain selectively heightened the animal's aversion to painful experiences (affective pain), as measured in the place escape/avoidance test, although no changes were observed in the sensory dimension of pain. In addition, electrophysiological recordings of LC neurons showed a low tonic but exacerbated nociceptive-evoked activity when the injured paw was stimulated. These changes were accompanied by an increase in tyrosine hydroxylase and gephyrin expression in the LC. Furthermore, intra-LC administration of bicuculline, a c-aminobutyric acid-A receptor antagonist, attenuated the negative affective effects of pain. These data show that changes in the LC are greater than those expected from the simple summation of each independent factor (pain and stress), revealing mechanisms through which stressors may exacerbate pain perception without affecting the sensorial dimension. Ó

Chronic Social Stress Time-Dependently Affects Neuropathic Pain-Related Cold Allodynia and Leads to Altered Expression of Spinal Biochemical Mediators

“…Concerning our failure to identify differences in mechanical sensitivity between CCI and OSS+CCI groups, it is interesting to note that Bardin et al (2009) as well as Bravo et al (2012, 2013) reported similar findings in a model of chronic mild stress and in a model of social isolation. Whereas the temperature of the cold plate test (5°C) used in the present study quite selectively stimulates cold nociceptors of the C-fiber type (Simone and Kajander, 1996), the von Frey filaments may activate a larger range of nociceptors belonging both to the C- and A-delta fiber categories (Martin et al, 1997).…”

“…While some studies using psychological stressors observed an enhancement of pain sensitivity (Rivat et al, 2007; Burke et al, 2013), others failed to identify similar effects (Bravo et al, 2012, 2013). These divergent findings may partly be related to methodological differences with respect to the approaches chosen for stress induction.…”

“…In this context comorbidities between chronic stress and pain may also have to be considered (Sharp and Harvey, 2001; Shipherd et al, 2007). Recent preclinical studies have also shown that exposure to chronic stress may lead to an exacerbation of pain sensitivity (Shi et al, 2010; Bravo et al, 2013; Burke et al, 2013). …”

Pain exacerbates chronic mild stress-induced changes in noradrenergic transmission in rats

“…Although the absolute number of TH-IR neurons increased in CMS animals, our electrophysiological data revealed a decrease in their activity, a finding that should be confirmed in further studies measuring noradrenaline levels in the LC and projection areas (frontal cortex and spinal cord) in basal and evoked conditions (after a painful or stressful event). Furthermore, we detected no changes in NAT or α2-adrenoceptor expression, indicating that the changes observed in spontaneous activity are probably caused by another neurotransmitter, possibly GABA (Bravo et al, 2013;Dimitrov et al, 2013).…”

“…However, we observed increased avoidance of painful stimuli in animals subjected to CMS. Moreover, we subsequently demonstrated that in rats with neuropathic pain, social stress exacerbates aversion to painful experiences through a locus coeruleus (LC)-related mechanism (Bravo et al, 2013). Moreover, LC impairment coincides with the onset of anxio-depressive-like symptoms in rats suffering chronic neuropathic pain .…”