Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin
Introduction
Cannabinoids are the generic term for active compounds of Marijuana, of which Δ9-tetrahydrocannabinol (THC) is the most common representative. G-protein coupled cannabinoid receptor (CB1) have been identified first in the brain [1], [2] and spinal cord [3] of the rat. Administration of the endogenous cannabinoid receptor agonist anandamide [4], [5] elicited hypothermia, catalepsy, impaired motor activity and antinociception [6], [7], [8], [9], [10] and a central mode of action at CB1 has been discussed. Also, peripherally administered cannabinoids revealed anti-nociceptive and anti-hyperalgesic effects in rats [11] and humans [12], even though competitive binding studies with capsaicin (TRP-V1 receptor) [13], mustard oil (TRP-ANKTM1 receptor) [14], the CB1 receptor antagonist SR141716A [15] and researches with CB1 knock out mice [16] yielded that actions of particularly anandamide, an endogenous cannabinoid receptor agonist, are not being mediated by CB1 only.
In peripheral tissue, CB1 have been identified on neuronal and immune cells [17], [18]. On the latter – namely macrophages of the spleen and tonsils [19], [20], [21] – a particular cannabinoid receptor was determined that revealed about 40% receptor homology to CB1 only and therefore had been termed cannabinoid receptor 2 (CB2) [19]. According to their distribution, an activation of CB2 was associated with a modulation of the immune system [22] and functionally attributed to the treatment of, e.g. multiple sclerosis [23], [24] or the immune deficiency syndrome HIV [25]. However, therapeutic efficacy of cannabinoids in such clinical trials are still lacking [26].
In experimental studies on human tissue or cell lines some authors described the expression of CB1 and CB2. For instance, cannabinoid receptors have been determined in human pyramidal cells, T- and B-lymphocytes, keratinocytes, endothelial and epidermal cell lines [17], [27], [28], [29], [30], [31], but also in the intestine [32], [33] and corneal epithelium [34]. So far, no immunohistochemical study demonstrated the distribution of CB1 and CB2 in human cutaneous nerve fibers. Here, we investigated the presence and distribution of cannabinoid receptors in human cutaneous tissue and their localization on primary sensory nerves, appendage epithelial cells, cutaneous macrophages and skin mast cells.
Section snippets
Materials and methods
Biopsies of normal healthy skin (n = 10) from different sites of the body (leg, arm, trunk, face, capillitium) and of one case of mastocytosis were obtained from patients undergoing routine diagnostic and therapeutic surgery. Adult frontal rat brain including white and grey substance, cervical and thoracic spinal cord, and spleen served as a positive control (kindly provided by Prof. Dr. K.D. Richter, Dept. of Animal Experimental Research, University Hospital Münster, Germany). Rat tissue and
Small nerve fibers
CB1 was determined in cutaneous nerve fiber bundles. The staining protocol revealed strong reactivity for both Texas Red- and FITC-labelled secondary antibodies, and specificity of CB1 antibody was evidenced by replacement of the antibody with rabbit IgG serum and pre-absorption of the first antibody with the corresponding blocking peptide. Regardless the investigated tissue, i.e. rat brain, spinal cord, spleen and human skin, these control experiments did not result in any specific
Discussion
Numerous studies described the expression of cannabinoid 1 receptors in animal and human brain tissue [2], [35], [36], [37], [38], [39]. Their regional distribution had been associated with the psycho-active attributes of cannabinoids and their influence on emotion [40], [41]. In addition, identification of CB1 and CB2 in dorsal root ganglia cells of the rat [42], [43], [44], [45] suggested a cannabinoid receptor expression on primary afferent neurons [7], [46], [47], [48], [49], [50]. Even
Acknowledgement
The authors are grateful to Andrea Wissel for expert technical assistance.
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