Stimulation of spinal dorsal horn β2-adrenergic receptor ameliorates neuropathic mechanical hypersensitivity through a reduction of phosphorylation of microglial p38 MAP kinase and astrocytic c-jun N-terminal kinase

The noradrenaline-adrenergic system has a crucial role in controlling nociceptive transduction at the spinal level. While alpha-adrenergic receptors are known to regulate nociceptive neurotransmitter release at the spinal presynaptic level, it is not entirely clear whether beta-adrenergic receptors are involved in controlling pain transduction at the spinal level as well. The current study elucidated a role of beta-adrenergic receptors in neuropathic pain in mice following a partial sciatic nerve ligation (PSNL). In addition, the cellular and intracellular signaling cascade induced by beta-adrenergic receptors in neuropathic mice was elaborated. Intrathecal injection of isoproterenol (1 nmol), a nonselective beta-adrenergic receptor agonist, briefly ameliorated hind paw mechanical hypersensitivity of PSNL mice. Isoproterenol's antinociceptive effect was mediated through beta-adrenergic receptors since pretreatment with ICI118551, a selective beta 2-adrenergic receptor antagonist, but not with CGP20712A, a selective beta-adrenergic receptor antagonist, significantly attenuated isoproterenol's effect. Furthermore, intrathecal treatment with a selective beta 2-adrenergic receptor agonist, terbutaline, but not a selective beta 1 -adrenergic receptor agonist, dobutamine, also significantly ameliorated neuropathic pain. Fourteen days after PSNL, increased phosphorylation of both p38 Mitogen-activated protein kinase (MAPK) in microglia and c-jun N -terminal kinase (jNK) in astrocytes of ipsilateral spinal dorsal horn were observed. Phosphorylation of both microglial p38 MAPK and astrocytic INK were downregulated by stimulation of the beta 2-adrenergic receptor. Together, these results suggest that spinal beta 2-adrenergic receptor have an inhibitory role in neuropathic nociceptive transduction at the spinal level through a downregulation of glial activity, perhaps through modulation of MAP kinases phosphorylation. Thus, targeting of beta 2-adrenergic receptors could be an effective therapeutic strategy in treating neuropathic pain. (C) 2016 Elsevier Ltd. All rights reserved.