Uncovering molecular elements of brain–body communication during development and treatment of neuropathic pain

The hippocampus and TNF: Common links between chronic pain and depression

“…Constitutive levels of TNF␣ are present in the hippocampus (Ignatowski et al, 1997), but higher induced levels of this cytokine are associated with the development of chronic pain (Covey et al, 2000;Ignatowski et al, 1999;Sud et al, 2007). This higher pathological level of TNF␣ can be elicited experimentally; an increase in hippocampal TNF␣ levels temporally coincides with the development of thermal hyperalgesia in the CCI neuropathic pain model (Covey et al, 2000).…”

“…In hippocampi harvested from naïve animals, electrical field stimulation inhibits NE release, and activation of the ␣ 2 -AR further inhibits this release (Covey et al, 2000;Ignatowski et al, 1996a). Experimentally, during the development of neuropathic pain, inhibition of NE release from the hippocampus is more pronounced and NE concentrations released upon neuron stimulation remain low in the hippocampus due to enhanced ␣ 2 -AR activity (Covey et al, 2000;Spengler et al, 2007;Sud et al, 2007).…”

“…Whereas activation of ␤-ARs results in anti-inflammatory effects (Severn et al, 1992), activation of ␣ 2 -ARs is generally considered pro-inflammatory by triggering or enhancing an immune/inflammatory response (Spengler et al, 1990;Sud et al, 2007). Development of neuropathic pain is associated with enhanced sympathetic activity (Sasaki et al, 1997) and increased activation of ␣ 2 -ARs, which contributes to the increased production of TNF␣ .…”

“…Increased TNF level in the hippocampus decreases the hippocampal NE level (i) and decreases BDNF (j) (see Fig. 3), effects involved in the development of chronic pain and depression (Covey et al, 2000;Ignatowski et al, 1999;Reynolds et al, 2005a;Sud et al, 2007Sud et al, , 2008. Cytokines reduce both the number and the function of GRs and play a role in altering the negative feedback from the hippocampus (k) (Pariante et al, 1997;Raison et al, 2006;Raison and Miller, 2003).…”

“…Also, tricyclic antidepressants, atypical antidepressants (bupropion, rolipram), and electroconvulsive therapy directly reduce TNF levels in the brain (Brustolim et al, 2006;Buttini et al, 1997;Hestad et al, 2003;Ignatowski et al, 1996b;Ignatowski and Spengler, 1994;Nickola et al, 2001). The initial antidepressant-induced decrease in TNF expression is a cAMP-mediated event (Maes et al, 2005;Renauld et al, 2004;Sud et al, 2007). (b) Since TNF normally inhibits NE release, the initial decrease in TNF levels allows for an increase in NE release (Reynolds et al, 2004b).…”