Central projections of identified, unmyelinated (C) afferent fibers innervating mammalian skin

Unmyelinated (C) fibers are the most numerous sensory elements of mammalian peripheral nerve and comprise many of those responsible for initiating pain and temperature reactions; however, direct evidence has been lacking as to where and how these fibers terminate in the central nervous system. A plant lectin (Phaseolus vulgaris leukoagglutinin) was applied intracellularly by iontophoresis as an immunocytochemical marker. This permitted visualization of the central terminations of cutaneous C sensory fibers that had been identified by the nature of stimuli that excited them. The central branch of C-fiber units arborized and terminated mainly in the superficial layers of the spinal dorsal horn in defined patterns that related to their functional attributes. Thus, the superficial dorsal horn seems to act as a processing station for signals from fine sensory fibers.     

HCN2 ion channels play a central role in inflammatory and neuropathic pain

The rate of action potential firing in nociceptors is a major determinant of the intensity of pain. Possible modulators of action potential firing include the HCN ion channels, which generate an inward current, I(h), after hyperpolarization of the membrane. We found that genetic deletion of HCN2 removed the cyclic adenosine monophosphate (cAMP)-sensitive component of I(h) and abolished action potential firing caused by an elevation of cAMP in nociceptors. Mice in which HCN2 was specifically deleted in nociceptors expressing Na(V)1.8 had normal pain thresholds, but inflammation did not cause hyperalgesia to heat stimuli. After a nerve lesion, these mice showed no neuropathic pain in response to thermal or mechanical stimuli. Neuropathic pain is therefore initiated by HCN2-driven action potential firing in Na(V)1.8-expressing nociceptors.     

Somatosensory responses of bulboreticular units in awake cat: relation to escape-producing stimuli

In awake, unrestrained cats, bulboreticular neurons respond after electrical stimulation of cutaneous nerve with increasing discharge as stimulus intensity is raised to levels eliciting escape behavior. These cells discharge most vigorously to noxious natural somatic stimuli and are not driven by other sensory modalities. Electrical stimulation through the recording microelectrode also elicits escape, which further suggests bulboreticular participation in pain sensory mechanisms.     

Erasure of a spinal memory trace of pain by a brief, high-dose opioid administration

Painful stimuli activate nociceptive C fibers and induce synaptic long-term potentiation (LTP) at their spinal terminals. LTP at C-fiber synapses represents a cellular model for pain amplification (hyperalgesia) and for a memory trace of pain. μ-Opioid receptor agonists exert a powerful but reversible depression at C-fiber synapses that renders the continuous application of low opioid doses the gold standard in pain therapy. We discovered that brief application of a high opioid dose reversed various forms of activity-dependent LTP at C-fiber synapses. Depotentiation involved Ca(2+)-dependent signaling and normalization of the phosphorylation state of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This also reversed hyperalgesia in behaving animals. Opioids thus not only temporarily dampen pain but may also erase a spinal memory trace of pain.     

Failure of beta-adrenergic receptor blockade to prevent arrhythmias induced by sympathetic nerve stimulation

Cardiac arrhythmias produced by electrical stimulation of the ventrolateral cardiac sympathetic nerve in dogs were not blocked by the combined administration of propranolol and practolol in amounts that completely blocked cardiac beta-adrenergic receptors. Blockade of cardiac alpha-adrenergic receptors, as well as cardiac cholinergic receptors, also had no influence on the arrhythmias. These results suggest that the adrenergic neuroeffector junction is fundamentally different from any hitherto described, differing perhaps in the neurotransmitter involved or in the nature of the receptor.     

Temporary abolition of pain in man

In eight patients with intense chronic cutaneous pain, sensory nerves or roots. supplying the painful area were stimulated. Square-wave 0.1-millisecond pulses at 100 cycles per second were applied, and the voltage was raised until the patient reported tingling in the area. During this stimulation, pressure on previously sensitive areas failed to evoke pain. Four patients, who had diseases of their peripheral nerves, experienced relief of their pain for more than half an hour after stimulation for 2 minutes.     

鸡颈皮神经的感觉神经元和交感节后神经元—HRP法研究

此项研究用了体重1.0～2.5kg的成年母鸡18只,以追寻鸡颈皮神经的感觉神经元和交感节后神经元。将C_6～C_(11)皮神经断端浸渍于20％HRP溶液中2～3天以引入酶。取相应的颈交感干神经节和脊神经节及其前后相邻的神经节,制成厚50μm的连续冰冻切片。TMB反应,明视野光镜观察。标记的交感节后神经元胞体出现于与酶引入皮神经相连的交感干神经节。少数出现于相邻的后一个交感神经节。标记的脊神经感觉神经元胞体只出现于与酶引入皮神经相连的脊神经节。     

Effect of reserpine pretreatment on stimulation of the accelerans nerve of the dog

Pretreatment with two doses of reserpine (each 0.1 mg/kg, intraperitoneally) sensitizes the heart to the positive chronotropic action of norepinephrine and reduces the response to stimulation of the accelerans nerve. Ganglionic transmission remains unaffected. The results indicate that the presence of certain stores of peripheral sympathetic transmitter is essential for the production of tachycardia by stimulation of the accelerans nerve.     

Analgesia from electrical stimulation in the brainstem of the rat

Stimulation at several mesencephalic and diencephalic sites abolished responsiveness to intense pain in rats while leaving responsiveness to other sensory modes relatively unaffected. The peripheral field of analgesia was usually restricted to one-half or to one quadrant of the body, and painful stimuli applied outside this field elicited a normal reaction. Analgesia outlasted stimulation by up to 5 minutes. Most electrode placements that produced analgesia also supported self-stimulation.One placement supported self-stimulation only in the presence of pain.     

Neuronal specification of cutaneous nerves through connections with skin grafts in the frog

Skin grafts were rotated 180 degrees in frog tadpoles. After metamorphosis, cutaneous reflexes were tested, and the receptive fields of cutaneous nerves were mapped electrophysiologically. Accurately localized limb movements were elicited by mechanical stimulation of normal skin, or of dorsal skin reimplanted on the back after 180-degree rotation. Reflexes misdirected to the original site of the stimulated skin were elicited from dorsoventrally inverted grafts, but not from anteroposteriorly inverted grafts. In most cases, the local nerves supplied the grafts, and each nerve entered the skin within its own receptive field. This observation eliminated the possibility that misdirected reflexes were due to selective regrowth of cutaneous nerves. We concluded that cutaneous nerves formed central synaptic associations which were specified by their new terminal connections with grafted skin.     

Guanosine 3',5'-monophosphate in sympathetic ganglia: increase assoicated with synaptic transmission

Brief stimulation of cholinergic preganglionic nerve fibers resulted in an increase in guanosine 3',5'-monophosphate (cyclic GMP) in the bullfrog sympathetic ganglion. When the release of synaptic transmitter was prevented by a high-magnesium, low-calcium Ringer solution, stimulation of preganglionic nerve fibers did not increase cyclic GMP in the ganglion. The increase in cyclic GMP caused by preganglionic stimulation was also blocked by the muscarinic antagonist, atropine. The data indicate that the increase in cyclic GMP is associated with synaptic transmission and support the possibility that cyclic GMP may mediate the postsynaptic action of acetylcholine at muscarinic cholinergic synapses.     

Potent analgesic effects of GDNF in neuropathic pain states

Neuropathic pain arises as a debilitating consequence of nerve injury. The etiology of such pain is poorly understood, and existing treatment is largely ineffective. We demonstrate here that glial cell line-derived neurotrophic factor (GDNF) both prevented and reversed sensory abnormalities that developed in neuropathic pain models, without affecting pain-related behavior in normal animals. GDNF reduces ectopic discharges within sensory neurons after nerve injury. This may arise as a consequence of the reversal by GDNF of the injury-induced plasticity of several sodium channel subunits. Together these findings provide a rational basis for the use of GDNF as a therapeutic treatment for neuropathic pain states.     

Pineal N-acetyltransferase activity: effect of sympathetic stimulation

Stimulation of preganglionic sympathetic fibers to the superior cervical ganglia elevates the activity of pineal N-acetyltransferase. After the stimulation-induced rise in enzyme activity, a return toward baseline levels occurs whether or not nerve stimulation is continued. The ability of pineal N-acetyltransferase activity to fall in the presence of stimulation may account for the persistence of its rhythm in blinded animals.     

Axonal elongation into peripheral nervous system "bridges" after central nervous system injury in adult rats

The origin, termination, and length of axonal growth after focal central nervous system injury was examined in adult rats by means of a new experimental model. When peripheral nerve segments were used as "bridges" between the medulla and spinal cord, axons from neurons at both these levels grew approximately 30 millimeters. The regenerative potential of these central neurons seems to be expressed when the central nervous system glial environment is changed to that of the peripheral nervous system.     

Arterial hypertension elicited by subpressor amounts of angiotensin

Long-term infusion of amounts of angiotensin insufficient at the beginning to raise arterial pressure results, after several days in sustained arterial hypertension in unanesthetized dogs. This hypertension is to a large degree dependent on environmental stimuli, and results chiefly from increase in peripheral resistance. As in dogs with renal hypertension, there is increased pressor responsiveness to tyramine. This indirect action of angiotensin to increase total peripheral resistance and arterial pressure by an action on the sympathetic nervous system, along with an upward resetting of the carotid sinus buffering mechanism, might logically account for the neural component of chronic renal hypertension. Such a proposal integrates the humoral and neural elements of the mosaic describing the mechanisms of tissue perfusion.     

Apolipoprotein E: cholesterol transport protein with expanding role in cell biology

Apolipoprotein E is a plasma protein that serves as a ligand for low density lipoprotein receptors and, through its interaction with these receptors, participates in the transport of cholesterol and other lipids among various cells of the body. A mutant form of apolipoprotein E that is defective in binding to low density lipoprotein receptors is associated with familial type III hyperlipoproteinemia, a genetic disorder characterized by elevated plasma cholesterol levels and accelerated coronary artery disease. Apolipoprotein E is synthesized in various organs, including liver, brain, spleen, and kidney, and is present in high concentrations in interstitial fluid, where it appears to participate in cholesterol redistribution from cells with excess cholesterol to those requiring cholesterol. Apolipo-protein E also appears to be involved in the repair response to tissue injury; for example, markedly increased amounts of apolipoprotein E are found at sites of peripheral nerve injury and regeneration. Other functions of apolipoprotein E, unrelated to lipid transport, are becoming known, including immunoregulation and modulation of cell growth and differentiation.     

Altered nociceptive neuronal circuits after neonatal peripheral inflammation

Nociceptive neuronal circuits are formed during embryonic and postnatal times when painful stimuli are normally absent or limited. Today, medical procedures for neonates with health risks can involve tissue injury and pain for which the long-term effects are unknown. To investigate the impact of neonatal tissue injury and pain on development of nociceptive neuronal circuitry, we used an animal model of persistent hind paw peripheral inflammation. We found that, as adults, these animals exhibited spinal neuronal circuits with increased input and segmental changes in nociceptive primary afferent axons and altered responses to sensory stimulation.     

Primary afferent depolarization evoked by a painful stimulus

Pulses of intense radiant heat applied to the plantar pad of unanesthetized spinal cats produced negative dorsal root potentials, increased excitability of cutaneous A fibers, and marked activation of ipsilateral flexor motoneurons. The same effects were obtained during cold block of A fiber conduction in the appropriate peripheral nerve. We conclude that adequate noxious activation of cutaneous C fibers depolarizes cutaneous A fibers.     

Parasympathetic ganglia: activation of an adrenergic inhibitory mechanism by cholinomimetic agents

Electrical stimulation of the sympathetic nerves to the urinary bladder or the intraarterial administration of the cholinomimetic substances acetylcholine or methacholine produced adrenergic inhibition in parasympathetic ganglia on the surface of the bladder. The inhibition appeared to be mediated, at least in part, via adrenergic inhibitory neurons located in the pelvic plexus. Atropine blocked the inhibitory response to injected cholinomimetic agents but did not alter the response to stimulation of the sympathetic nerves. Thus, the inhibitory neurons can be activated via both muscarinic and nonmuscarinic receptors, the latter being of primary physiological importance.     

Adrenal tyrosine hydroxylase: compensatory increase in activity after chemical sympathectomy

Destruction of peripheral sympathetic nerve endings with 6-hydroxydopamine causes a disappearance of cardiac tyrosine hydroxylase, accompanied by a twofold increase in adrenal tyrosine hydroxylase and a small increase in phenyl-ethanolanine-N-methyl transferase. No change in adrenal catecholamine content occurs under these conditions.