Neuroscience
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The present study was designed to investigate whether a state of neuropathic pain induced by sciatic nerve ligation could alter the rewarding effect, antinociception, and G-protein activation induced by a prototype of mu-opioid receptor agonist morphine in the mouse. The sciatic nerve ligation caused a long-lasting and profound thermal hyperalgesia. Under this neuropathic pain-like state, an i.c.v. morphine-induced place preference was observed in sham-operated mice but not in sciatic nerve-ligated mice. ⋯ Reverse transcription-polymerase chain reaction analysis showed that sciatic nerve ligation did not alter the mRNA product of mu-opioid receptors in the lower midbrain, indicating that a decrease in some mu-opioid receptor functions may result from the uncoupling of mu-opioid receptors from G-proteins. We found a significant increase in protein levels of G-protein-coupled receptor kinase 2, which causes receptor phosphorylation in membranes of the lower midbrain but not in the pons/medulla, obtained from mice with nerve injury, whereas there were no changes in the protein level of phosphorylated-protein kinase C in the lower midbrain. These results suggest that the uncoupling of mu-opioid receptors from G-proteins by G-protein-coupled receptor kinase 2 in the lower midbrain may, at least in part, contribute to the suppression of the rewarding effect of morphine under neuropathic pain.
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Electrophysiological recordings were used to investigate the effects of ATP analogues on theta-burst-induced long-term potentiation (LTP) in rat hippocampal slices. alpha,beta-Methylene ATP (alpha,beta-MeATP; 20 microM) decreased LTP from 36+/-9% to 17+/-5%, an effect prevented by adenosine A(1) receptor blockade in accordance with the localised catabolism of ATP analogues into adenosine, leading to adenosine A(1) receptor activation. Thus, to probe the role of extracellular ATP, all experiments were performed with the A(1) receptor selective antagonist, 1,3-dipropyl-8-cyclopentylxanthine (50 nM). In these conditions, alpha,beta-MeATP or 5'-adenylylimido-diphosphate (beta,gamma-ImATP; 20 microM) facilitated LTP by 120%, an effect prevented by the P2 receptor antagonists, pyridoxalphosphate-6-azophenyl-2'-4'-disulphonic acid (PPADS; 20 microM) or suramin (75 microM), as well as by the P2X(1/3)-selective antagonist 8-(benzamido)naphthalene-1,3,5-trisulfonate (10 microM). ⋯ Furthermore, beta,gamma-ImATP (20 microM) enhanced [(3)H]adenosine outflow from rat hippocampal slices by nearly 150%, an effect prevented by PPADS (20 microM) or suramin (75 microM). The adenosine transport inhibitors, nitrobenzylthioinosine (5 microM) and dipyridamole (10 microM) also prevented beta,gamma-ImATP (20 microM)-induced [(3)H]adenosine outflow and facilitation of LTP. These results suggest that ATP analogues facilitate LTP through P2 receptor activation that mainly triggers adenosine release leading to the activation of adenosine A(2A) receptors.
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Converging evidence in schizophrenia suggests prefrontal cortical neuronal deficits that correlate with exaggerated subcortical dopamine (DA) functions: Excitotoxic lesion of the ventral hippocampus (VH) in neonatal rats is widely considered a putative animal model of schizophrenia as they lead to characteristic post-pubertal emergence of behavioral and cognitive abnormalities suggesting a developmental change in the neural circuits comprising the prefrontal cortex (PFC) and subcortical DA. Nerve growth factor inducible-B (NGFI-B, also known as Nur77), an orphan nuclear receptor and transcriptional regulator, is constitutively expressed in the target structures of DA pathways. It acts as an immediate early gene with rapid modulation of its mRNA expression by stress, DA and antipsychotic drugs. ⋯ Amphetamine treatment increased the expression of NGFI-B mRNA in the mPFC, CC, striatum and NAcc in both control and lesioned animals of both ages. Interestingly, however, striatal and NAcc regions of lesioned rats showed a significantly greater effect of amphetamine at PD56. The data suggest that nVH lesions lead to delayed changes in PFC gene expression along with functional DAergic hyperactivity in subcortical regions.
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Comparative Study
Sexual dimorphism in the contribution of protein kinase C isoforms to nociception in the streptozotocin diabetic rat.
The contribution of second messenger signaling, glucose level and sex hormones to sexual dimorphism in the streptozotocin model of diabetic painful peripheral neuropathy was evaluated. Streptozotocin induced elevation of blood glucose and mechanical hyperalgesia (measured by the Randall-Selitto paw-withdrawal test) were both greater in female rats. Ovariectomy abolished and estrogen implants reconstituted this sexual dimorphism; gonadectomy in males had no effect. ⋯ Inhibitors of protein kinase A, protein kinase C (non-selective), protein kinase G and nitric oxide synthase attenuated hyperalgesia equally in both sexes. Higher blood glucose levels in diabetic females were also sex hormone dependent, and magnitude of hyperalgesia correlated with blood glucose level in diabetic male and female rats. These results demonstrate sexual dimorphism in diabetic hyperalgesia, mediated by sex hormone dependent differences in protein kinase Cepsilon and protein kinase Cdelta signaling and blood glucose levels and suggest that sex may be an important factor to be considered in the treatment of symptomatic diabetic neuropathy.
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Comparative Study
Attenuation of neuropathic manifestations by local block of the activities of the ventrolateral orbito-frontal area in the rat.
Clinical and recent imaging reports demonstrate the involvement of various cerebral prefrontal areas in the processing of pain. This has received further confirmation from animal experimentation showing an alteration of the threshold of acute nociceptive reflexes by various manipulations in the orbito-frontal cortical areas. The present study investigates the possible involvement of this area in the modulation of neuropathic manifestations in awake rats. ⋯ Our results correlate well with the established connections of the ventrolateral orbital area with the thalamic nucleus subnucleus involved in the procession of thermal nociception. The transient effects reported following permanent lesions in the orbital areas may reflect its flexible role in pain modulation. This observation provides further evidence on the plasticity of the neural networks involved in the regulation of nociceptive behavior.