The Dendritic Release Of Neuroactive Peptides From Dendritic Branches Of Primary Sensory Neurons

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The final historical example of dendritic release of neuroactive substances is that of the peripheral branches of primary sensory neurons whose receptor/transducer terminations correspond to dendritic profiles according to Ramon y Cajal's interpretation

(1904) and Bodian's (1962) more contemporary classification. These branches, as described in any Neuroscience textbook, gather environmental signals which are eventually transformed into nerve impulses. However, as discussed above, these dendritic sensory branches were additionally noted early on to have an "antidromic" (against the direction of the neuronal polarity) effector activity. This effect was classically described as the "sensory antidromic vasodilatator response". Dale hypothesized that a chemical compound released from these sensory peripheral branches was causing the antidromic vasodilation (Dale, 1935). They did not reflect in their considerations on the dendritic nature of these terminations. Sir Henry Dale hoped that the investigation of these branches could lead to the identification of "the" sensory transmitter in the CNS. The realization of that vision had to wait for the identification of neuroactive peptides as transmitter candidates.

In the thirties, Von Euler and Gaddum (1931) discovered from tissue extracts a chemically unidentified substance with pharmacological effects which included vasodilation. This unknown substance was later named substance P. Lembeck (1953) found that the substance P-like material was enriched in dorsal roots of sensory ganglia and speculated that substance P was indeed "the" sensory transmitter. This concept was introduced by Otsuka and collaborators (1972) in a series of elaborate electrophysiological studies made even prior to the chemical identification of substance P.

The actual nature of the substance P had to wait for the chemical identification and characterization by Leeman and co-workers who described it as a peptide of eleven amino acids of the tachykinin family (Chang et al., 1971). The development of high affinity antibodies against the known substance P peptide allowed Thomas Hokfelt to define the substance P localization sites in the CNS and periphery. Immunoreactivity to substance P was described by Hokfelt et al (1975) in the periphery, in locations compatible with the sensory nature of these processes. With Marina Del Fiacco and George Paxinos, we were able to demonstrate experimentally that the resection of the purely sensory branch of the mental nerve abolished substance P immunoreactivity in peripheral fibres providing evidence for its sensory localization in peripheral dendritic terminals (Cuello et al., 1978). Furthermore, the peptide was observed in the cell bodies of the primary sensory neurons of the spinal cord and trigeminal system (Hokfelt et al., 1975; Del Fiacco and Cuello, 1980) as well as in the CNS in superficial layers of the dorsal horn of the spinal cord localizations which were compatible with the sensory nature of the newly discovered neuroactive peptide (Hokfelt et al., 1975; Cuello et al., 1978). Early after the identification of substance P, a transport mechanism of substance P immunoreactive material towards the periphery was demonstrated for primary sensory neurons (Takahashi and Otsuka, 1975; Hokfelt et al, 1975; Gamse et al., 1979a). Lembeck and Holzer (1979) pointed out that the potent substance P vasodilatory effects are very similar to those resulting from the antidromic stimulation of mixed nerves (Lembeck and Holzer, 1979). More direct evidence supporting the hypothesis that substance P plays a key role in the sensory-elicited antidromic vasodilation came from the application of the first reported substance P antagonists which were capable of inhibiting the antidromic vasodilation both in the saphenous (Lembeck, Donnerer and Bartho, 1982) and in the trigeminal (Couture and Cuello, 1984) sensory peripheral territories. Furthermore, the application of capsaicin (8-methyl-N-vanillyl-6-nonemide) known at the time to be a potent activator of chemo-sensitive peripheral sensory fibers led to desensitization of sensory fibers (Jancso et al., 1967). We demonstrated that this agent was capable of depleting to near totality the immunoreactivity to substance P in presumptive sensory fibers at their point of entry in the spinal cord (Jessell et al., 1978). The neonatal application of capsaicin was shown to elicit a marked impairment of the vasodilatory responses following antidromic stimulation (Lembeck and Holzer, 1979; Gamse et al., 1979b). Nowadays there is abundant evidence for a peripheral effector role of "dendritically" released substance P and a number of neuroactive peptides from peripheral branches of sensory neurons. The current view is that sensory peptides are locally released to facilitate the passage of blood borne substances (plasma extravasation) to respond to peripheral noxia. This mechanism is central to what is known as neurogenic inflammation and might be involved in a number of pathological conditions as varied as migraine and disturbances of the upper airways.

A more complex case of "dendritically" located neuroactive peptides is that of substance P in sensory ganglia. Sympathetic ganglia are richly innervated by substance P-immunoreactive fibers (Hokfelt et al., 1977). We established that in the prevertebral ganglia these substance P-immunoreactive fibers originate in sensory neurons of the dorsal root ganglia by cutting the lumbar splanchnic nerves, while the severance of the hypogastric or colonic nerves produced no obvious changes (Baker et al., 1980; Matthews and Cuello, 1982). These fibers were affected by the application of capsaicin (Gamse et al., 1981; Matthews and Cuello, 1982). Electron microscopy of these peripheral sensory terminals in the prevertebral sympathetic ganglia revealed clear indications of conventional substance P immunoreactive presynaptic sites (Matthews and Cuello, 1982). This synaptic configuration of substance P immunoreactive sensory branch fibres in sympathetic ganglia was consistent with the electrophysiological findings of Otsuka and collaborators (Tsunoo et al., 1982) showing a substance P induced depolarization resembling non-cholinergic slow EPSP in the sympathetic ganglia. The existence of these sensory dendritic synapses in the sympathetic ganglia might be the structural and electrophysiological basis for postulated enteric-automonic reflexes.

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