Neuropharmacology
-
Behavioral sensitization, or augmented locomotor response to successive drug exposures, results from neuroadaptive changes contributing to addiction. Both the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) influence behavioral sensitization and display increased immediate-early gene and BDNF expression after psychostimulant administration. Here we investigate whether mPFC neurons innervating the VTA exhibit altered Fos or BDNF expression during long-term sensitization to amphetamine. ⋯ Similarly, more Fos-FG and Fos-BDNF double-labeling was observed in the mPFC of sensitized rats compared to drug-naïve rats after amphetamine challenge. Repeated amphetamine treatment also increased VTA BDNF, while both acute and repeated amphetamine treatment increased Fos and Fos-BDNF co-labeling, an effect enhanced in sensitized rats. These findings point to a role of cortico-tegmental BDNF in long-term amphetamine sensitization.
-
Comparative Study
Inhibition of ERK phosphorylation by substance P N-terminal fragment decreases capsaicin-induced nociceptive response.
Previous research has demonstrated that substance P N-terminal fragments produced by the action of several different enzymes in the spinal cord could reduce nociception when injected intrathecally (i.t.) into mice. The present study examined the possible involvement of spinal extracellular signal-regulated protein kinase (ERK), a mitogen-activated protein kinase (MAPK), in i.t. substance P (1-7)-induced antinociception as assayed by the capsaicin test. The i.t. injection of substance P (1-7) (20-80 nmol) into mice resulted in a dose-dependent attenuation of paw-licking/biting behavior induced by intraplantar injection of capsaicin, which was reversed by co-injection of [D-Pro(2), D-Phe(7)]substance P (1-7), a D-isomer and antagonist of substance P (1-7). ⋯ In parallel to the behavioral results, i.t. substance P (1-7) inhibited capsaicin-induced ERK phosphorylation, which was reversed by [D-Pro(2), D-Phe(7)]substance P (1-7), a substance P (1-7) antagonist. Both nociceptive behavioral response and spinal ERK activation induced by intraplantar capsaicin were reduced by U0126, an upstream inhibitor of ERK phosphorylation. Taken together, these findings suggest that the activation of ERK, but not p38 and JNK MAPKs in the spinal cord, contributes to intraplantar capsaicin-induced nociception, and that blocking ERK activation via substance P (1-7) binding sites may provide significant antinociception at the spinal cord level.
-
Comparative Study
The influence of manipulations to alter ambient GABA concentrations on the hypnotic and immobilizing actions produced by sevoflurane, propofol, and midazolam.
Recent studies have suggested that extrasynaptic GABA(A) receptors, which contribute tonic conductance, are important targets for general anesthetics. We tested the hypothesis that manipulations designed to alter ambient GABA concentrations (tonic conductance) would affect hypnotic (as indicated by loss of righting reflex, LORR) and immobilizing (as indicated by loss of tail-pinch withdrawal reflex, LTWR) actions of sevoflurane, propofol, and midazolam. Two manipulations studied were 1) the genetic absence of glutamate decarboxylase (GAD) 65 gene (GAD65-/-), which purportedly reduced ambient GABA concentrations, and 2) the pharmacological manipulation of GABA uptake using GABA transporter inhibitor (NO-711). ⋯ NO-711 (3 mg/kg, ip) enhanced the duration of LORR and LTWR by propofol and midazolam, but not sevoflurane. Patch-clamp recordings revealed that sevoflurane (0.23 mM) slightly enhanced the amplitude of tonic GABA current in the frontal cortical neurons; however, these effects were not strong enough to alter discharge properties of cortical neurons. These results demonstrate that ambient GABA concentration is an important determinant of the hypnotic and immobilizing actions of propofol and midazolam in mice, whereas manipulations of ambient GABA concentrations minimally alter cellular and behavioral responses to sevoflurane.
-
Comparative Study
Cardiovascular effects of chronic treatment with a β2-adrenoceptor agonist relieving neuropathic pain in mice.
Neuropathic pain is often a chronic condition, disabling and difficult to treat. Using a murine model of neuropathic pain induced by placing a polyethylene cuff around the main branch of the sciatic nerve, we have shown that chronic treatment with β-AR agonists is effective against neuropathic allodynia. β-mimetics are widely used against asthma and chronic obstructive pulmonary disease and may offer an interesting option for neuropathic pain management. The most prominent adverse effects of chronic treatment with β-mimetics are cardiovascular. ⋯ Our data show that a chronic treatment with the β(2)-AR agonist terbutaline at low antiallodynic dose does not affect cardiovascular parameters, whereas the mixed β(1)/β(2)-AR agonist isoproterenol induces cardiac hypertrophy. These data suggest that low doses of β(2)-AR agonists may provide a suitable treatment with rare side effects in neuropathic pain management. This study conducted in an animal model requires clinical confirmation in humans.
-
Comparative Study
GPR3 orphan receptor is involved in neuropathic pain after peripheral nerve injury and regulates morphine-induced antinociception.
GPR3 is an orphan G-protein coupled receptor broadly expressed in brain structures controlling emotional-like behaviors and pain. GPR3 receptor up-regulates cAMP and promotes neurite outgrowth in mammalian neurons, being a good candidate to participate in the pathophysiology of neurodegenerative diseases as well as brain and spinal cord injuries. In this study, we evaluated the role of GPR3 receptor in the development and expression of neuropathic pain after sciatic nerve ligature, and the inflammatory reaction in the dorsal horn of the spinal cord in both Gpr3-/- and Gpr3+/+ mice. ⋯ Taken together, our results demonstrate, for the first time, the involvement of the orphan GPR3 receptor in the expression and development of neuropathic pain and in the analgesia induced by morphine. The lack of GPR3 receptors produced hypersensitivity to thermal non-noxious and noxious stimuli without affecting the spinal inflammatory response associated to sciatic nerve injury and reduced morphine antinociception in the tail immersion test. Our findings propose GPR3 receptors as a new molecular target in neuropathic pain therapy as well as a new component of a pro-opioid receptor system.