GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex

Abstract

Trigeminal neuropathic pain is described as constant excruciating facial pain. The study goal was to investigate the role of nucleus locus coeruleus (LC) in a model of chronic orofacial neuropathic pain (CCI-ION). The study examines LC's relationship to both the medullary dorsal horn receiving trigeminal nerve sensory innervation and the medial prefrontal cortex (mPFC). LC is a major source of CNS noradrenaline (NA) and a primary nucleus involved in pain modulation. Although descending inhibition of acute pain by LC is well established, contribution of the LC to facilitation of chronic neuropathic pain is also reported. In the present study, a rat orofacial pain model of trigeminal neuropathy was induced by chronic constrictive injury of the infraorbital nerve (CCI-ION). Orofacial neuropathic pain was indicated by development of whisker pad mechanical hypersensitivity. Hypersensitivity was alleviated by selective elimination of NA neurons, including LC (A6 cell group), with the neurotoxin anti-dopamine-β-hydroxylase saporin (anti-DβH-saporin) microinjected either intracerebroventricularly (i.c.v.) or into trigeminal spinal nucleus caudalis (spVc). The GABA A receptor antagonist, bicuculline, administered directly into LC (week 8) inhibited hypersensitivity. This indicates a valence shift in which increased GABA A signaling ongoing in LC after trigeminal nerve injury paradoxically produces excitatory facilitation of the chronic pain state. Microinjection of NAα1 receptor antagonist, benoxathian, into mPFC attenuated whisker pad hypersensitivity, while NAα2 receptor antagonist, idazoxan, was ineffective. Thus, GABA A -mediated activation of NA neurons during CCI-ION can facilitate hypersensitivity through NAα1 receptors in the mPFC. These data indicate LC is a chronic pain generator. Published by Elsevier Ltd on behalf of IBRO.

The noradrenergic locus coeruleus as a chronic pain generator

“…The locus coeruleus (LC), containing by far the greatest number of noradrenergic neurons in the brain, could be described by many as a “pain suppressor.” We refer the reader to excellent comprehensive overviews of the basic science that describes the contribution of the LC to the inhibition of acute and chronic pain (Pertovaara, ; Llorca‐Torralba et al, ). By contrast, the current review argues that, after traumatic nerve injury, the LC is not an inhibitor but instead becomes a chronic neuropathic “pain generator.” In support of this opposing position, we emphasize two of our own studies, using standard models of neuropathic pain following traumatic injury to the sciatic or trigeminal nerves (Brightwell and Taylor, ; Kaushal et al, ), as well as several others. This topic is interesting given our stance that facilitation increases over time after nerve injury, and the lack of knowledge surrounding the underlying mechanisms that cause the transition from acute to chronic pain.…”

“…Similarly, intracerebroventricular administration of anti‐DβH‐saporin but not control IgG‐saporin, given 3 weeks after CCI‐ION surgery, reduced behavioral signs of mechanical hypersensitivity for at least 1 month after initiation of treatment (Kaushal et al, ). Taken together, these data indicate that the LC facilitates both the development and maintenance of neuropathic pain following injury to the sciatic or trigeminal nerves (Brightwell and Taylor, ; Kaushal et al, ).…”

“…Similarly, intracerebroventricular administration of anti‐DβH‐saporin but not control IgG‐saporin, given 3 weeks after CCI‐ION surgery, reduced behavioral signs of mechanical hypersensitivity for at least 1 month after initiation of treatment (Kaushal et al, ). Taken together, these data indicate that the LC facilitates both the development and maintenance of neuropathic pain following injury to the sciatic or trigeminal nerves (Brightwell and Taylor, ; Kaushal et al, ). However, because intracerebroventricular injection of anti‐DβH‐saporin will disrupt both ascending (e.g., A1 and A2) as well as descending (A5, A6, A7) noradrenergic pathways, further studies were required to determine whether the LC contributes to allodynia or hyperalgesia via ascending projections, lateral projections to other brainstem sites, or descending projections to the spinal cord.…”

Zerumbone Modulates α2A-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models

“…In normal conditions, the noradrenergic system primarily functions to inhibit nociceptive transmission. Following nerve injury, the plastic changes that occur shift the inhibitory tone of the noradrenergic system to facilitate nociceptive transmission instead (Brightwell and Taylor, 2009;Kaushal et al, 2016). Therefore, the increase in expression of a 2A -adrenoceptor following CCI in vehicle-treated group may be due to plastic changes that occur, abolishing the inhibitory tone of the noradrenergic system.…”

GPR30 receptor promotes preoperative anxiety-induced postoperative hyperalgesia by up-regulating GABAA-α4β1δ subunits in periaqueductal gray in female rats

“…Accumulating evidence has indicated that GABA A -mediated activation of neurons facilitates hypersensitivity in the central nervous system (CNS) [11]. Study has shown the up-regulation of GABA A α4 subunit is associated with anxiety disorders in the female rat [12].…”