Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy

BACKGROUND: The reduction of gamma-aminobutyric acid (GABA) type A receptor-mediated inhibition has long been implicated in spinal sensitization of nociceptive responses. However, it is largely unknown which signaling cascades in spinal dorsal horn neurons are initiated by the reduced inhibition to trigger pain hypersensitivity.METHODS: GABAergic inhibition was manipulated by intrathecal application of GABA type A receptor antagonist bicuculline in intact mice or by GABA type A receptor agonist muscimol in complete Freund's adjuvant-injected mice. Immunoblotting, coimmunoprecipitation, immunohistochemistry, and behavioral tests were used to explore the signaling pathways downstream of the altered GABAergic tone.RESULTS: The study data revealed that the 61-kD isoform of striatal-enriched protein phosphatase (STEP61) was a key molecule that relayed the signals from GABAergic neurotransmission. The authors found that STEP61 was highly expressed in dorsal horn neurons. Under physiological conditions, STEP61 tonically interacted with and negatively controlled the activities of extracellular signal-regulated kinase and Src-family protein tyrosine kinases member Fyn, two critical kinases involved in spinal sensitization. Once GABAergic inhibition was impaired, STEP61 interaction with its substrates was substantially disturbed, allowing for activation of extracellular signal-regulated kinase and Fyn (n = 4 to 6). The hyperactivities of extracellular signal-regulated kinase and Fyn, along with STEP61 dysregulation, caused the tyrosine phosphorylation and synaptic accumulation of GluN2B subunit-containing N-methyl-D-aspartate subtype of glutamate receptors (n = 6), leading to GluN2B receptor-dependent pain hypersensitivity. Overexpression of wild-type STEP61 to resume its enzymatic activity significantly blocked the mechanical allodynia evoked by bicuculline and more importantly, alleviated chronic inflammatory pain (n = 6 in each group).CONCLUSION: These data identified STEP61 as a key intermediary for GABAergic inhibition to regulate pain sensitization.

GABAergic inhibition regulated pain sensitization through STEP61 signaling in spinal dorsal horn of mice.

Dexmedetomidine relieves formaldehyde-induced pain in rats through both α2 adrenoceptor and imidazoline receptor.

Introduction: Mediators in pain transmission are the targets of a multitude of different analgesic pharmaceuticals. This review explores the most significant mediators of pain transmission as well as the pharmaceuticals that act on them.Areas covered: The review explores many of the key mediators of pain transmission. In doing so, this review uncovers important areas for further research. It also highlights agents with potential for producing novel analgesics, probes important interactions between pain transmission pathways that could contribute to synergistic analgesia, and emphasizes transmission factors that participate in transforming acute injury into chronic pain.Expert commentary: This review examines current pain research, particularly in the context of identifying novel analgesics, highlighting interactions between analgesic transmission pathways, and discussing factors that may contribute to the development of chronic pain after an acute injury.

/pdf/transmission-pathways-and-mediators-as-the-basis-for-4fshteap6p.pdf

Transmission pathways and mediators as the basis for clinical pharmacology of pain

Roles of Phosphorylation of N-Methyl-d-Aspartate Receptor in Chronic Pain

α2 noradrenergic receptor suppressed CaMKII signaling in spinal dorsal horn of mice with inflammatory pain

Focal adhesion kinase (FAK) is one of the nonreceptor protein tyrosine kinases critical for the dynamic regulation of cell adhesion structures. Recent studies have demonstrated that FAK is also localized at excitatory glutamatergic synapses and is involved in long-term modification of synaptic strength. However, whether FAK is engaged in nociceptive processing in the spinal dorsal horn remains unresolved. The current study shows that intraplantar injection of complete Freund's adjuvant (CFA) in mice significantly increases FAK autophosphorylation at Tyr397, indicating a close correlation of FAK activation with inflammatory pain. FAK activation depended on the activity of N-methyl-D-aspartate-subtype glutamate receptor (NMDAR) and metabotropic glutamate receptor (mGluR) because pharmacological inhibition of NMDAR or group I mGluR totally abolished FAK phosphorylation induced by CFA. The active FAK operated to stimulate extracellular signal-regulated kinase1/2 (ERK1/2), which boosted the protein expression of GluN2B subunit-containing NMDAR at the synaptosomal membrane fraction. Inhibition of FAK activity by spinal expression of a kinase-dead FAK(Y397F) mutant repressed ERK1/2 hyperactivity and reduced the synaptic concentration of NMDAR in CFA-injected mice. Electrophysiological recording demonstrated that intracellular loading of specific anti-FAK antibody significantly reduced the amplitudes of NMDAR-mediated excitatory postsynaptic currents on lamina II neurons from inflamed mice but not from naive mice. Behavioral tests showed that spinal expression of FAK(Y397F) generated a long-lasting alleviation of CFA-induced mechanical allodynia and thermal hyperalgesia. These data indicate that FAK might exaggerate NMDAR-mediated synaptic transmission in the spinal dorsal horn to sensitize nociceptive behaviors.

Peripheral inflammation activated focal adhesion kinase signaling in spinal dorsal horn of mice

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α2 noradrenergic receptor suppressed CaMKII signaling in spinal dorsal horn of mice with inflammatory pain

Peripheral inflammation activated focal adhesion kinase signaling in spinal dorsal horn of mice