The gap junction blocker carbenoxolone attenuates nociceptive behavior and medullary dorsal horn central sensitization induced by partial infraorbital nerve transection in rats

Abstract

Glial cells are being increasingly implicated in mechanisms underlying pathological pain and recent studies suggest glial gap junctions involving astrocytes may contribute. The aim of the present study was to examine the effect of a gap junction blocker carbenoxolone (CBX) on medullary dorsal horn (MDH) nociceptive neuronal properties and facial mechanical nociceptive behavior in a rat trigeminal neuropathic pain model involving partial transection of the infraorbital nerve (p-IONX). p-IONX produced facial mechanical hypersensitivity reflected in significantly reduced head withdrawal thresholds that lasted for over 3 weeks. p-IONX also produced central sensitization in MDH nociceptive neurons that was reflected in significantly increased receptive field size, reduction of mechanical activation threshold and increases in noxious stimulation-evoked responses. Intrathecal CBX treatment significantly attenuated the p-IONX-induced mechanical hypersensitivity and the MDH central sensitization parameters, compared to intrathecal vehicle treatment. These results provide the first documentation that gap junctions may be critically involved in orofacial neuropathic pain mechanisms.

Intrathecal carbenoxolone inhibits neuropathic pain and spinal wide-dynamic range neuronal activity in rats after an L5 spinal nerve injury

“…This finding is in line with a previous observation that CBX reduces medullary dorsal horn neuronal response to mechanical stimulation after mustard oil application to the tooth pulp[22]. Further, a recent study showed that CBX inhibited mechanical hypersensitivity in a rat model of orofacial neuropathic pain[38]. Pain hypersensitivity induced by trigeminal nerve injury and SNL may involve different mechanisms.…”

Neuron–Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region

“…Cx43 expression in astroglia increases following injury ( Figure 3 ) to the trigeminal nerve, and intrathecal administration of a gap junction blocker attenuates the central sensitization of nociceptive neurons in the trigeminal subnucleus caudalis [ 108 , 109 ], indicating increased communication among astroglial cells. Furthermore, activated microglia may also activate astroglia.…”

Oral 2‐hydroxyoleic acid inhibits reflex hypersensitivity and open–field‐induced anxiety after spared nerve injury

“…OA and its derivatives activate PPARs (Guzman et al, 2004), while the activation of the PPAR-γ subtype leads to a reduction in glia activation and behavioural hypersensitivity following SNI (Morgenweck et al, 2013). OA also inhibits gap junction permeability in astrocytes (Lavado et al, 1997) and 2-OHOA could reduce the impact of glia activation on the maintenance of behavioural hypersensitivity after SNI (Wang et al, 2014). OA also inhibits gap junction permeability in astrocytes (Lavado et al, 1997) and 2-OHOA could reduce the impact of glia activation on the maintenance of behavioural hypersensitivity after SNI (Wang et al, 2014).…”

“…OA is also superior when compared to polyunsaturated fatty acids in reducing lipid peroxidation (Hart et al, 1991) and for the inhibition of glial superoxide radical production (Chan et al, 1988). OA also inhibits gap junction permeability in astrocytes (Lavado et al, 1997) and 2-OHOA could reduce the impact of glia activation on the maintenance of behavioural hypersensitivity after SNI (Wang et al, 2014). Microglia cells are also a major constitutive source of leukotriene B4 in vitro (Matsuo et al, 1995), while in vivo it mediates mechanical hypersensitivity after SNI (Okubo et al, 2010).…”