Primary Afferent Presynaptic Receptors

Stimulation of 5-HT4 receptors on the presynaptic terminal of submucosal intrinsic primary afferent nerves enhances the release of their neurotransmitters, including calcitoningene-related peptide, which stimulate second-order enteric neurons to promote the peristaltic reflex (Figure 62-4). These enteric neurons stimulate proximal bowel contraction (via acetylcholine and substance P) and distal bowel relaxation (via nitric oxide and vasoactive intestinal peptide). 

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). 

In the brain stem, TRPV1 receptor activation, similarly to P2X3 receptor activation (see above), facilitated spontaneous glutamate release in a tetrodotoxin- and Cd2+-insensitive manner, even though the two presynaptic receptors were located on different primary afferent fibres (Jin et al. 2004). Action potential-dependent glutamate release, in contrast, was reduced by TRPV 1 activation (Doyle et al. 2002). In paraventricular neurons, TRPV 1 receptor activation facilitated spontaneous glutamate release in a tetrodotoxin- and Cd2+-insensitive way, but in that case evoked glutamate release was enhanced too (Li et al. 2004). 

Duguid IC, Smart TG (2004) Retrograde activation of presynaptic NMDA receptors enhances GABA release at cerebellar intemeuron-Purkinje cell synapses. Nat Neurosci 7 525 Eccles JC, Kostyuk PG, Schmidt RF (1962) Central pathways responsible for depolarization of primary afferent fibres. J Physiol 161 237-57... 

Li D, Ren Y, Xu X, Zou X, Fang L, Lin Q (2008) Sensitization of primary afferent nociceptors induced by intradermal capsaicin involves the peripheral release of calcitonin gene-related peptide driven by dorsal root reflexes. J Pain 9 1155-1168 Li DP, Chen SR, Pan YZ, Levey Al, Pan HL (2002a) Role of presynaptic muscarinic and GABAB receptors in spinal glutamate release and cholinergic analgesia in rats. J Physiol (Lond) 543 807-818... 

Ohishi H, Nomura S, Ding Y-Q. Shigemoto R, Wada E, Kinoshita A, Li J-L, Neki A, Nakanishi S, Mizuno N (1995b) Presynaptic localization of a metabotropic glutamate receptor, mGluR7, in the primary afferent neurons an immunohistochemical study in the rat. Neurosci Lett 262 85-88. 

Opioid receptors are also located presynaptically on primary afferents (type C and Ag fibers) in the dorsal horn of the spinal cord. Activation of these receptors —release of substance P, a peptide neurotransmitter that causes excitatory actions in pain pathways. Opioid receptors involved in spinal analgesia are of both p and K subtypes. 

At the same time, several other mechanisms may be activated to compensate for some of the excitatory effect, perhaps to keep the system from being hyperreactive. These mechanisms include (1) presynaptic inhibition of glutamate release from the primary afferent terminals, (2) activation of the NKl receptors on the soma/dendrite of GABAergic intemeurons to enhance GABA release, and (3) an enhanced glycine synaptic transmission via an enhanced glycine receptor function through a protein kinase C or a Ca/calmodulin dependent protein kinase 11 pathway (Fig. 2). 

Opioid-induced analgesia is produced through the action of opioid receptors on presynaptic terminals of the C-fibers and A-delta fibers. These fibers, which transmit nociceptive messages, are inhibited by the indirect effects of opioids, which in turn reduce the release of neurotransmitters such as substance P, CGRP, and glutamate. This effect occurs in the peripheral nervous system as well as at the primary afferent terminals in the spinal cord. 

Merighi A, Bardoni R, Salio C et al (2008) Presynaptic functional trkB receptors mediate the release of excitatory neurotransmitters from primary afferent terminals in lamina II (substantia gelatinosa) of posmatal rat spinal cord. Dev Neurobiol 68 457-475... 

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... 

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