Neuroscience
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Comparative Study
Response properties of dorsal root reflexes in cutaneous C fibers before and after intradermal capsaicin injection in rats.
C fiber dorsal root reflexes (DRR) contribute to neurogenic inflammation and possibly also to touch-evoked pain (allodynia) induced by intradermal capsaicin. The responses of C fibers in the sural nerve to graded mechanical stimuli before and following intradermal capsaicin were studied in 39 adult male rats. Two-thirds of 111 fibers were without spontaneous activity, while the remaining fibers averaged 1.41+/-0.25 spontaneous antidromic spikes per second. ⋯ Mechanical stimuli re-applied following the resumption of spontaneous discharges failed to produce any response. Spontaneous DRRs were increased by topical application of 1 mM beta-alanine (a competitive antagonist for GABA transporters) and abolished by ipsilateral spinal nerve L5 lesion, verifying antidromic origin. The role of C fiber DRRs in normal sensory transmission and during hyperalgesia is discussed.
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Opiates produce analgesia by activating mu opioid receptor-linked inhibitory G protein signaling cascades and related ion channel interactions that suppress cellular activities by hyperpolarization. After chronic opiate exposure, an excitatory effect emerges contributing to analgesic tolerance and opioid-induced hyperalgesia. Ultra-low-dose opioid antagonist co-treatment blocks the excitatory effects of opiates in vitro, as well as opioid analgesic tolerance and dependence, as was demonstrated here with ultra-low-dose naloxone combined with morphine. ⋯ Although chronic morphine decreased Gi/o coupling by mu opioid receptors, a pronounced coupling to Gs emerged coincident with a Gbetagamma interaction with adenylyl cyclase types II and IV. Co-treatment with ultra-low-dose naloxone attenuated both the chronic morphine-induced Gs coupling and the Gbetagamma signaling to adenylyl cyclase, while increasing Gi/o coupling toward or beyond vehicle control levels. These findings provide a molecular mechanism underpinning opioid tolerance and dependence and their attenuation by ultra-low-dose opioid antagonists.
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GABA(B) receptors are believed to play a role in rhythmic activity in the mammalian brain. The aim of our study was to examine the presynaptic and postsynaptic locations of these receptors in the medial septal diagonal band area (MS/DB), an area known to pace the hippocampus theta rhythm. Whole-cell patch recordings were made from parasagittal MS/DB slices obtained from the 16-25 day rat. ⋯ Baclofen, also at a concentration too low to elicit postsynaptic activity, reduced the frequencies and amplitudes of spontaneous IPSCs and EPSCs recorded in the presence of 200-400 nM kainate. Rhythmic compound IPSCs at theta frequencies were recorded under these conditions in some neurons, and these rhythmic compound IPSCs were disrupted by the activation but not by the inhibition of GABA(B) receptors. These results suggest that GABA(B) receptors modulate rather than generate rhythmic activity in the MS/DB, and that this modulatory effect occurs via receptors located on presynaptic terminals.
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The present studies aimed to determine whether cocaine- and amphetamine-regulated transcript (CART) peptide in the nucleus of accumbens shell (AcbSh) is implicated in the regulation of food intake. Bilateral intranuclear injections of CART peptide (55-102, 1 microg/microl/side) into the AcbSh decreased food intake with no change in locomotion activity and attenuated the orexigenic effect of the GABA(A) agonist muscimol (100 ng/microl/side) in male Sprague-Dawley rats. Decreased food intake after bilateral intranuclear injections of CART was more sustained in freely fed rats than in food-deprived rats, suggesting fuel availability is an important factor in modulating the function of CART in the regulation of feeding. ⋯ Moreover, many of these efferent cells contain CART immunoreactivity, including those which reside within the AcbSh, suggesting that accumbal CART circuitry is involved in the central function of the nucleus accumbens. Furthermore, fasting suppressed CART mRNA levels in the AcbSh, paraventricular nucleus of the hypothalamus, arcuate nucleus, and the perifornical region, indicating that the Acb is sensitive to fuel availability to an extent similar to those regions in the hypothalamus. Our findings are the first to demonstrate that CART mRNA in the AcbSh is sensitive to metabolic challenges and that injection of CART peptide into the AcbSh has an inhibitory effect on food intake.
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Comparative Study
Spinal phospholipase A2 in inflammatory hyperalgesia: role of the small, secretory phospholipase A2.
Current work emphasizes that peripheral tissue injury and inflammation results in a heightened sensitivity to subsequent noxious input (hyperalgesia) that is mediated in large part by the spinal synthesis and release of eicosanoids, in particular prostaglandins. Secreted phospholipase A(2)s (sPLA(2)s) form a class of structurally related enzymes that release arachidonic acid from cell membranes that is further processed to produce eicosanoids. We hypothesized that spinal sPLA(2)s may contribute to inflammation-induced hyperalgesia. ⋯ IT LY311727 also suppressed thermal hyperalgesia induced by IT injection of substance P (30 nmol). Using in vivo spinal microdialysis, we found that IT injection of LY311727 attenuated prostaglandin E(2) release into spinal dialysate otherwise evoked by the IT injection of substance P. Taken together, this work points to a role for constitutive sPLA(2)s in spinal nociceptive processing.