Spinal cord primary afferents

Substance P is a member of a group of polypeptides known as neurokinins or tachykinins. It is thought to be the primary neurotransmitter for the transfer of sensory information from the periphery to the spinal cord and brain. Substance P as well as neurokinin NKX receptors has been detected in vagal afferent neurons in the area postrema, nucleus tractus solitarius and dorsal motor nucleus of the vagus. Substance P has been shown to increase the firing rate of neurons in the area postrema and nucleus tractus solitarius and to produce retching when applied directly to these areas in animal studies. 

Figure 1.6 Presynaptic inhibition of the form seen in the dorsal horn of the spinal cord, (a) The axon terminal (i) of a local neuron is shown making an axo-axonal contact with a primary afferent excitatory input (ii). (b) A schematic enlargement of the synapse, (c) Depolarisation of the afferent terminal (ii) at its normal resting potential by an arriving action potential leads to the optimal release of neurotransmitter, (d) When the afferent terminal (ii) is already partially depolarised by the neurotransmitter released onto it by (i) the arriving acting potential releases less transmitter and so the input is less effective...

The somatosensory primary afferent fibre, which conveys sensory information to the spinal cord, can be classified into several classes, according to the transduction... 

GABAergic presynaptic inhibition of excitatory transmission of primary afferent neurones of the spinal cord resulting in epileptiform convulsions, myosis, and dyspnea with more or less prolonged apnea. 

The areas expressing // receptor mRNA corresponded to those found to express // receptor binding sites and // receptor immunoreactivity [37—41]. In most brain and spinal cord regions, // receptor immunoreactivity was detected in cell bodies and dendrites of neurons [39—41]. Immunoreactivity was also detected in superficial layers of the dorsal hom, which contain primary afferent sensory input /x re-... 

Carstens, E., Klumpp, D., Randic, M., and Zimmerman, M. (1981) Effect of iontophoretically applied 5-hydroxytryptamine on the excitability of single primary afferent C- and A-fibers in the cat spinal cord. Brain Res., 220 151-158. 

In addition to the physiological process of autoinhibition, another mechanism of presynaptic inhibition has been identified in the peripheral nervous system, although its precise relevance to the brain is unclear. In the dorsal horn of the spinal cord, for example, the axon terminal of a local neuron makes axo-axonal contact with a primary afferent excitatory input, which leads to a reduction in the neurotransmitter released. This is due to the local neuron partly depolarizing the nerve terminal, so that when the axon potential arrives, the change induced is diminished, thereby leading to a smaller quantity of transmitter being released. In the brain, it is possible that GABA can cause presynaptic inhibition in this way. 

The nervous system is divided into two parts the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and spinal cord. The PNS consists of all afferent (sensory) neurons, which carry nerve impulses into the CNS from sensory end organs in peripheral tissues, and all efferent (motor) neurons, which carry nerve impulses from the CNS to effector cells in peripheral tissues. The peripheral efferent system is further divided into the somatic nervous system and the autonomic nervous system. The effector cells innervated by the somatic nervous system are skeletal muscle cells. The autonomic nervous system innervates three types of effector cells (1) smooth muscle, (2) cardiac muscle, and (3) exocrine glands. While the somatic nervous system can function on a reflex basis, voluntary control of skeletal muscle is of primary importance. In contrast, in the autonomic nervous system voluntary control can be exerted, but reflex control is paramount. 

Benzodiazepines also possess muscle relaxant activity. Their pharmacology is discussed in Chapter 30. Diazepam Valium) has been used for control of flexor and extensor spasms, spinal spasticity, and multiple sclerosis. The muscle relaxant effect of the benzodiazepines may be mediated by an action on the primary afferents in the spinal cord, resulting in an increased level of presynaptic inhibition of muscle tone. Polysynaptic reflexes are inhibited. The most troublesome side effect is drowsiness, which is dose dependent. Tolerance to both the therapeutic effects and the side effects develops. 

Schematic diagram of a primary afferent neuron mediating pain, its synapse with a secondary afferent in the spinal cord, and the targets for local pain control. The primary afferent neuron cell body is not shown. At least three nociceptors are recognized acid, injury, and heat receptors. The nerve ending also bears opioid receptors, which can inhibit action potential generation. The axon bears sodium channels and potassium channels (not shown), which are essential for action potential propagation. Synaptic transmission involves release of substance P, a neuropeptide (NP) and glutamate and activation of their receptors on the secondary neuron. Alpha2 adrenoceptors and opioid receptors modulate the transmission process.

Diazepam Facilitates GABAergic transmission in central nervous system (see Chapter 22) Increases interneuron inhibition of primary motor afferents in spinal cord central sedation Chronic spasm due to cerebral palsy, stroke, spinal cord injury acute spasm due to muscle injury Hepatic metabolism duration, 12-24 h Toxicities See Chapter 22... 

In the spinal cord, a2-agonists act on receptors located on the terminals of primary afferent fibers in the dorsal horn substantia gelatinosa to reduce nociceptive transmission by inhibiting the release of glutamate and substance P (Collin et al., 1994 Hamalainen and Pertovaara, 1995) (see Fig. 2). These receptors appear to be primarily of the a2A subtype which is negatively coupled to adenylate cyclase (Lakhlani et al., 1997 see Millan, 1999 but see Sawamura et al., 2000, and references therein for a discussion of the possible involvement of other a2-receptor subtypes in antinociception). Like activation of p-opioid receptors, the activation of a2-receptors increases the potassium conductance of the cells bearing these receptors, thus reducing cellular excitability. 

Recently, it has been shown that spinal neurons express functional kainate receptors which contribute to synaptic transmission between primary afferent fibers and dorsal horn neurons (Li et al., 1999). Administration of the AMPA/kainate antagonist CNQX to the spinal cord... 

Surprisingly, the vanilloid receptor ligand capsaicin supplied the first experimental evidence for the association between SP and nociception (Gasparovic et al., 1964). Capsaicin depletes small primary afferents of at least SP, if not all of their peptide content, and this was accompanied by hypoalgesia. SP depolarizes the ventral root of an isolated rat spinal cord preparation (Konishi and Otsuka, 1974), and has also been shown to excite and/or depolarize neurons in the dorsal root (Urban et al., 1985). Furthermore, in studies on the larger laminae IV and V neurons, the selective agonist, [Sar9,... 

Dendrobine at a dose of 3 X 10-5 M reduced the dorsal root potential and reflex. It provoked a mild hyperpolarization in both dorsal and ventral roots of frog isolated spinal cord. It affected the (3-alanine- and taurine-induced depolarization of primary afferent terminals and reversibly blocked the presynaptic inhibition caused by antidromic conditioning stimulation of the ventral root potential induced by repetitive antidromic stimulation of ventral root and lowered maximum. It would be interesting to learn whether further research of the Dendrobium species discloses any alkaloid interfering with the glycinergic system, an aspect discussed under the following heading. 

Opioids basically exert their analgesic effects by inhibiting synaptic transmission in key pain pathways in the spinal cord and brain. This inhibitory effect is mediated by opioid receptors that are located on both presynaptic and postsynaptic membranes of pain-mediating synapses (Fig. 14—2). In the spinal cord, for example, receptors are located on the presynaptic terminals of primary (first-order) nociceptive afferents, and when bound by opioids, they directly decrease the release of pain-mediating transmitters such as substance P.35,38 Opioid drug-receptor interactions also take place on the postsynaptic membrane of the secondary afferent neuron—that is, the second-order nociceptive afferent neuron in the spinal cord.19,33 When stimulated, these receptors also inhibit pain transmission by hyperpolarizing the postsynaptic neuron.19... 

Small quantities of opiate injected intrathecally or epidurally produce segmental analgesia. This observation led to the clinical use of spinal and epidural opiates during surgical procedures and for the relief of postoperative and chronic pain. As with local anesthesia, analgesia is confined to sensory nerves that enter the spinal cord dorsal horn in the vicinity of the injection. Presynaptic opioid receptors inhibit the release of substance P and other neurotransmitters from primary afferents, whereas postsynaptic opioid receptors decrease the activity of certain dorsal horn neurons in the spinothalamic tracts. 

However, presynaptic NMDA autoreceptors may also mediate opposite effects, i.e., a reduction of glutamate release. At parallel fiber Purkinje cell synapses, activation of presynaptic NMDA receptors caused significant reductions in excitatory postsynaptic currents (Casado et al. 2002). Likewise, spontaneous and evoked glutamate release from the nerve endings of primary afferents in the spinal cord was reduced when presynaptic NMDA receptors were activated (Bardoni et al. 2004). In contrast to this, substance P release at such synapses was shown to be enhanced by the activation of presynaptic NMDA receptors (Liu et al. 1997). 

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