Stephen H. Buck

Substance P in the cerebral vasculature: depletion by capsaicin suggests a sensory role

Abstract Measurements of substance P immunoreactivity confirms the presence of substance P-containing nerve fibers within the wall of cerebral blood vessels of guinea pigs, cats and rabbits. Low levels of somatostatin were also found in cerebral arteries of cats and rabbits. After treatment of guinea pigs with capsaicin, substance P levels in the cerebral circulation were markedly reduced, as was substance P in the mesenteric artery. Depletion of substance P by capsaicin suggests that cerebral arteries are innervated by primary afferent neurons, with a possible role in headache or reaction to trauma.

Neuropeptides in sensory neurons

Substance P, somatostatin, VIP, CCK, angiotensin II, and bombesin have all been localized by immunohistochemical or radioimmunological means in neurons of sensory ganglia or in the dorsal horn of the spinal cord. Most of these neuropeptides have electrophysiological effects on spinal neurons and for substance P and somatostatin, these effects have been associated with particular sensory modalities. Newer investigations using the compound capsaicin are consistent with the hypothesis that substance P is an important neurochemical mediator of certain kinds of noxious peripheral stimuli. The newly described substance P antagonists promise to be important pharmacological tools for investigation of the long-neglected neurochemical bases of sensory neuron function. Elaboration of the roles of these sensory neuropeptides will no doubt shed light on many disease states in which there seems to be sensory neuron involvement.

Capsaicin: hot new pharmacological tool

The article by S. H. Buck and T. F. Burks (TIPS 4, 84-87) is a good overview of recent investigations and will probably have a stimulating effect on further research. Therefore, it is necessary to clarify some points to avoid confusion or misinterpretation. This is the second review in which cap, saicin has been called a derivative of homovanillic acid. In fact, capsaicin is the acylamide of vanillylamine and 8-methyl-6 trans-nonenoic acid. Acylamides of homovanillic acid are able to produce iden- tical effects to those of capsaicin 1, but the difference in chemical structure should not be ignored. To he precise, capsaicin is not a new pharmacological tool, because it has been used for this purpose by the group of the late Nicholas Jancs6 (who is the father of G. Jancs6, cited in the article) for more than three decades. It is certainly true that inter- esting new aspects (selective substance P depletion and interaction with nerve growth factor) have only recently been discovered. It should also he stressed that capsaicin is a selective, useful tool in vitro. Capsaicin- sensitive neural responses of isolated organs can be completely abolished by the drug without affecting adrenergic, cholinergic, purinergic, or even some pep, tidergic neural responses. The irreversible nature of the blockade and the more than 1 000 times concentration range of its neurone-selective effect is particularly use- rid. The variety of methods of application of capsaicin is one of the main advantages of the drug. Its neurone-selective effect on sensory neurones resembles that of guanethidine on adrenergic neurones (neurone blockade with depletion after ini- tial excitation of the nerve endings, fol- lowed by similar ultrastructural changes after higher doses, or even neurotoxic degeneration when it is given to neonates). On the basis of this analogy capsaicin and its congeners have been classified as sen- sory neurone blocking agents 1.

A survey of substance P, somatostatin, and neurotensin levels in aging in the rat and human central nervous system ☆

Levels of the neuropeptides substance P, somatostatin, and neurotensin were measured by radioimmunoassay in regions of the rat and human central nervous system (CNS) in aging. Somatostatin levels were significantly lower only in the corpus striatum of older rats. Substance P levels and neurotensin levels were generally stable with aging as were levels of somatostatin in regions other than the corpus striatum. In post-mortem human CNS tissues, no significant negative correlations of levels of the three peptides were observed with time to refrigeration or time to freezer for the samples. In the human CNS, there were no significant age-related alterations in substance P levels in frontal cortex, thalamus, hypothalamus, caudate nucleus, globus pallidus, or substantia nigra. There was a significant age-related decrease in substance P levels in the human putamen. This age-related decrease was not present in tissues from victims of Huntingtons disease nor was there any striking difference in substance P levels as a function of duration of the disease. There were no significant age-related changes in somatostatin levels in human frontal cortex, caudate nucleus, putamen, medial globus pallidus, or substantia nigra. Among these same regions, there was a significant age-related decrease in neurotensin levels only in the pars compacta and pars reticulata of the human nigra. These, results implicate neuropeptides in aging processes in certain regions of the CNS. There are differences between rats and humans with respect to neuropeptides in the aging process in the CNS. Deterioration of some neuropeptide pathways in and to human basal ganglia may be involved in the suspected functional deterioration of parts of the extrapyramidal system in aging.

Reduction in basal ganglia and substantia nigra substance P levels in Huntington's disease

Substance P (SP) levels were determined by radioimmunoassay (RIA) in several regions of post-mortem brain of controls and Huntingtons disease (HD) patients. In controls, highest SP levels were found in basal ganglia, substantia nigra and hypothalamus. Nigral pars reticulata contained 3--4-fold higher levels than pars compacta. In HD, SP levels were reduced in all basal ganglia and substantia nigra. The reductions ranged from 48% in caudate nucleus to over 90% in nigral pars reticulata. There were no changes in SP levels in HD frontal cortex, thalamus or hypothalamus.

Depletion of primary afferent substance P by capsaicin and dihydrocapsaicin without altered thermal sensitivity in rats

Systemic administration of capsaicin and dihydrocapsaicin to adult rats of two different strains and of capsaicin to neonatal rats, depleted substance P levels in dorsal roots plus ganglia and in dorsal spinal cord. In no case was this depletion accompanied by substantially altered tail-flick latencies. The results are not consistent with a role of the neuropeptide in nociceptive thermal sensitivity in the rat.

High-affinity 3H-substance P binding to longitudinal muscle membranes of the guinea pig small intestine

The binding of 3H-substance P (3H-SP) to longitudinal muscle membranes of the guinea pig small intestine has been characterized. The binding of 3H-SP exhibited a high affinity (Kd = 0.5nM). It was saturable (Bmax = 2 fmoles/mg tissue), reversible, and temperature-dependent. Kinetic studies and competition of 3H-SP binding by unlabeled SP yielded Kd and Ki values, respectively, which were in good agreement with the Kd calculated from saturation studies. The binding of 3H-SP appeared to be dependent on the presence of divalent cations in the incubation buffer. It was displaced by SP and various analogs and fragments in the rank order of SP greater than SP-(2-11) = SP-(3-11) greater than Nle11- SP = physalaemin greater than SP-(4-11) greater than SP-(5-11) greater than eledoisin much greater than SP-(7-11). Our results indicate that 3H-SP binds in longitudinal muscle of the guinea pig small intestine to a biologically relevant receptor which in many respects resembles the SP receptor characterized in the brain and the salivary gland of the rat.

Thermal analgesia and substance P depletion induced by capsaicin in guinea-pigs

Abstract Treatment of adult guinea-pigs with subcutaneous doses of capsaicin of 1, 5, 50, 200, 200, 500, 500 mg/kg in daily succession increased skin flinch latency and depleted substance P from dorsal root ganglia. Similar treatment of animals with doses of 50, 100, 100, 100, 100 mg/kg significantly increased skin flinch latency and hot-plate escape latency and depleted substance P from dorsal root ganglia and dorsal spinal cord. Capsaicin had no effect on levels of substance P in other CNS regions or in any region of the gastrointestinal tract. Responses to mechanical pressure were not altered by capsaicin treatment. Depletion of primary afferent substance P in guinea-pigs appears to result in substantial thermal antinociception without producing comparable pressure antinociception.

Capsaicinoid-induced local and systemic antinociception without substance P depletion.

Capsaicin and its analog, dihydrocapsaicin, produced chemogenic and thermal antinociception and depletion of substance P from the dorsal spinal cord and dorsal root ganglia of guinea pigs following a single parenteral dose. Time course and distribution studies indicated that capsaicinoid-induced antinociception resulted from neither depletion of substance P nor nonspecific actions of capsaicinoids at dorsal root ganglia. A site of action for capsaicinoid-induced antinociception is peripheral to the dorsal root ganglia and may involve covalent binding of capsaicinoids to free nerve endings of the dermis. Depletion of substance P by capsaicinoids appears to be mediated at a site more central than that which mediates antinociception and may involve alterations in the retrograde axoplasmic transport of neurotrophic factors.

Light microscopic autoradiographic localization of [3H] substance P binding sites in rat thoracic spinal cord

We have used light microscopic autoradiography to look for the distribution of [3H] substance P receptors in the thoracic spinal cord of the rat. High densities of autoradiographic grains were localized to the intermedialateral cell column, the central canal and the substantia gelatinosa of the dorsal horn.