Antinociception mediated by α2-adrenergic activation involves increasing tumor necrosis factor α (TNFα) expression and restoring TNFα and α2-adrenergic inhibition of norepinephrine release

Abstract

The central component that establishes chronic pain from peripheral nerve injury is associated with increased tumor necrosis factor-α (TNFα) production in the brain. This study examined TNFα and its reciprocally permissive role with α 2 -adrenergic activation during peak and progressive decline of thermal hyperalgesia in sciatic nerve chronic constriction injury (CCI). Accumulation of TNFα mRNA (in situ hybridization) increases in the hippocampus and locus coeruleus during the onset of neuropathic pain and persists as hyperalgesia abates. Activation of α 2 -adrenergic receptors in control rats decreases TNFα mRNA accumulation in these brain regions. In contrast, during hyperalgesia, α 2 -adrenergic activation enhances TNFα mRNA accumulation. Whether this enhanced TNFα production is associated with changes in the regulation of norepinephrine (NE) release was tested. Hippocampal slices were electrically depolarized to evaluate α 2 -adrenergic and TNFα regulation of NE release. While inhibition of NE release by TNFα is maximal during peak hyperalgesia, it subsequently transforms to facilitate NE release. In addition, α 2 -adrenergic receptor activation with clonidine (0.2 mg/kg, i.p.) in CCI rats experiencing hyperalgesia restores TNFα and α 2 -adrenergic inhibition of NE release. While TNFα directs the development of hyperalgesia, it also directs its resolution. Transformed sensitivity to α 2 -adrenergic agonists during hyperalgesia demonstrates a mechanism for therapy.

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

“…The decrease in pain is associated with a full switch in ␣ 2 -adrenergic and TNF␣ regulation of NE release from inhibition to potentiation of NE release from adrenergic neurons in the hippocampus. This switch or reversal of function counteracts the decrease in NE release that occurs during the development of hyperalgesia (Covey et al, 2000;Ignatowski et al, 2005;Spengler et al, 2007).…”

“…(a) Initially (acute), upon dosing, some antidepressants indirectly decrease TNF through blockade of monoamine reuptake or monoamine oxidase inhibition. This blockade increases NE availability allowing for ␣2-AR activation (it is coupled to G␣ i/o protein); the ␣2-AR-G␣ i/o configuration supports a decrease in TNF (see 'd' above) (Ignatowski et al, 1996a;Nickola et al, 2000;Renauld and Spengler, 2002;Reynolds et al, 2005a;Spengler et al, 2007). 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).…”

“…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).…”

“…The presynaptic ␣2-adrenergic receptor (␣2-AR) that normally favors coupling to G␣ i and inhibition of NE release becomes supersensitized, which allows for greater inhibition of NE release (Covey et al, 2000;Ignatowski et al, 1999Ignatowski et al, , 2005Nickola et al, 2000;Reynolds et al, 2004b). (d) A deficiency in bioavailable NE results in the attenuation of ␣2-AR stimulation that upon activation normally inhibits TNF expression (Ignatowski et al, 1996a;Nickola et al, 2000;Renauld and Spengler, 2002;Reynolds et al, 2005a;Spengler et al, 2007); therefore, ␣2-AR-mediated decrease in TNF is also attenuated, and a sustained elevation in TNF ensues. (e) TNF causes a decrease in hippocampal BDNF, CREB, and ␤-arrestin activity; the decrease in ␤-arrestin activity prevents desensitization of the G-protein-coupled receptor (␣2-AR-G␣ i/o ) (Khoa et al, 2006).…”

418 the Clinical and Laboratorial Evaluation of Transdermal Ketamine, Fentanyl, Clonidine or Their Combination in Chronic Low Back Pain

“…It has been demonstrated that stress-produced hormones (such as noradrenaline) in the blood serum served as indirect criteria of the functional activity of the endogenic antinociceptive structures before and after the treatment 4 only T clonidine (CloG) did not show any decrease in plasma noradrenaline levels. Although α2-adrenergic receptor activation with clonidine in rats experiencing hyperalgesia inhibited noradrenaline release 13 , and clonidine resulted in dose-dependent noradrenaline decrease 14 , by 6-h evaluation the dose used resulted in no evident decrease of noradrenaline by itself. However, the same dose further enhanced nordrenaline decrease after T fentanyl at 3-h evaluation.…”