Brain research
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Physiological experiments were run to examine the effects of noxious thermal stimulation of one hindpaw on the tail-flick reflex in the lightly anesthetized rat. Male Sprague-Dawley rats were anesthetized with an i.p. injection of a mixture of Na-pentobarbital (20 mg/kg) and chloral hydrate (120 mg/kg). After baseline readings were taken in the tail-flick test, either a non-noxious or a noxious stimulus was applied which consisted of immersion of one hindpaw in water at 40, 45, 50 or 55 degrees C for 1.5 min. ⋯ The increase in reaction time in response to immersion at 55 degrees C was attenuated or blocked by the novel, nonpeptide substance P (NK-1) receptor antagonist, CP-96,345, administered s.c. 30 or 60 min, respectively, prior to paw immersion. Similar injection of CP-96,344, the inactive stereoisomer, had no effect on the response, while another NK-1 receptor antagonist, CP-99,994, also attenuated the antinociceptive effect of the immersion. The increase in reaction time induced by immersion at 55 degrees C was absent in animals treated neonatally with capsaicin.(ABSTRACT TRUNCATED AT 250 WORDS)
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In freshly isolated spinal dorsal horn (DH) neurons (laminae I-IV) of the young rat, the effects of dynorphin A1-17, U-50,488H and U-69,593 on inward currents induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) were studied under whole-cell voltage-clamp conditions. When the cells were clamped to a holding potential of -60 mV, co-application of dynorphin A1-17 (10(-6) M) and AMPA (2 x 10(-5) M) reversibly decreased the peak amplitude of the initial transient component of the AMPA-induced current in 72% of the examined cells. In addition, dynorphin (10 microM) in perforated patch-recordings consistently produced a decrease in the steady-state component of the AMPA response. ⋯ Pretreatment of DH neurons with pertussis toxin blocked the depressant action of dynorphin A1-17, indicating that a Gi- or Go-type G protein was required for this effect on AMPA-activated currents. Intracellular dialysis with a highly specific peptide inhibitor (peptide 6-22) of the cAMP-activated protein kinase (PKA), and with Rp-cAMPS, prevented the depressant effect of dynorphin A1-17. In addition, staurosporine, a nonselective kinase inhibitor, blocked the dynorphin depression of the AMPA response.(ABSTRACT TRUNCATED AT 400 WORDS)
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Activation of the trigeminovascular system leads to neurogenic inflammation within the dura mater and cerebral vasodilatation. These processes have been implicated in the pathogenesis of migraine headache. Neurogenic vasodilator responses to trigeminal ganglion stimulation were investigated in rat facial skin, an area innervated by the trigeminal nerve. ⋯ However, neither the neurokinin-1 (NK1) receptor antagonist, RP67580 (0.23 or 2.3 mumol.kg-1, i.v.) nor the vasoactive intestinal peptide (VIP) antagonist, [p-Cl-D-Phe6,Leu17]-VIP (15 or 30 nmol.kg-1, i.v.) had any effect on these responses. These results suggest that CGRP is the major neuropeptide involved in the vasodilator response to trigeminal ganglion stimulation in rat facial skin. Clarification of the mechanisms involved in this neurogenic vasodilator response may aid the development of drugs that target the trigeminovascular system during migraine headache.
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Met-Enkephalin, which can be induced by estrogen in the ventromedial nucleus of hypothalamus (VMH), has been proposed to help mediate estrogenic action on lordosis behavior by acting on midbrain periaqueductal gray (PAG) neurons. Also, in the PAG, GABA may locally regulate the levels of lordosis behavior through GABAA receptors. Therefore, we examined the effects of both Met-enkephalin and GABA-related agents on neuronal activity of PAG neurons in slices. ⋯ Moreover, 76% of neurons inhibited by enkephalin were found to be tonically inhibited by endogenous GABA through GABAA receptors. It is argued, therefore, that increased enkephalinergic influences from the VMH to the PAG in estrogen-treated females could participate in the PAG neuronal control of lordosis by acting on the same neurons as are innervated by intrinsic GABAergic neurons. Since GABAA agonists actually facilitate lordosis in the PAG, these PAG neurons inhibited by both GABA and enkephalin may themselves facilitate behaviors which are antagonistic to lordosis, such as defensive behaviors.
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We tested the ability of Mg2+ therapy to block the heat-hyperalgesia, mechano-allodynia and mechano-hyperalgesia that are seen in rats with an experimental painful peripheral neuropathy (the CCI model of Bennett and Xie). Systemic Mg2+ (magnesium sulfate, 600 mg/kg, s.c.) significantly reduced heat-hyperalgesia and mechano-allodynia for 2-24 h post-injection, but had no effect on mechano-hyperalgesia. Intrathecal (i.t.) injections of Mg2+ (185-750 micrograms) at the level of the lumbar spinal cord significantly reduced heat-hyperalgesia, but perineural application (750 and 7,000 micrograms) to the site of nerve injury had no effect. ⋯ Mg2+ had any effect on the responses from the control, sham-operated side. We conclude that Mg2+ has a spinal site of action. Mg2+ therapy may be of limited use in the treatment of human painful peripheral neuropathy.