Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin

https://doi.org/10.1016/j.jdermsci.2005.01.007Get rights and content

Summary

Background:

Cannabinoid receptors mediate the psychopharmacological action of marijuana and have been localized in the central and peripheral nervous system as well as on cells of the immune system.

Objective:

Up to now, two cannabinoid receptors (CB1 and CB2) have been cloned and recent studies on animal tissue gave evidence for the presence of cannabinoid receptors in the skin.

Methods:

In the present immunohistochemical investigation we determined the precise localization of CB1 and CB2 in sections of human skin and in one case of mastocytosis.

Results:

CB1 and CB2 immunoreactivity was observed in cutaneous nerve fiber bundles, mast cells, macrophages, epidermal keratinocytes, and the epithelial cells of hair follicles, sebocytes and eccrine sweat glands. In epidermal keratinocytes, hair follicle and sebaceous glands, CB1 and CB2 were distributed in a complementary fashion. Double-immunostaining with an anti-CGRP antibody suggested the presence of cannabinoid receptors on small afferent peptidergic nerves.

Conclusion:

The abundant distribution of cannabinoid receptors on skin nerve fibers and mast cells provides implications for an anti-inflammatory, anti-nociceptive action of cannabinoid receptor agonists and suggests their putatively broad therapeutic potential.

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.

References (74)

  • T.M. Westlake et al.

    Cannabinoid receptor binding and messenger RNA expression in human brain: an in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer's brains

    Neuroscience

    (1994)
  • D. Bridges et al.

    Localisation of cannabinoid receptor 1 in rat dorsal root ganglion using in situ hybridisation and immunohistochemistry

    Neuroscience

    (2003)
  • A.G. Hohmann et al.

    Pre- and postsynaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord

    Brain Res

    (1999)
  • J. Ahluwalia et al.

    Cannabinoid 1 receptors are expressed in nociceptive primary sensory neurons

    Neuroscience

    (2000)
  • A. Dogrul et al.

    ‘Knock-down’ of spinal CB1 receptors produces abnormal pain and elevates spinal dynorphin content in mice

    Pain

    (2002)
  • T.P. Malan et al.

    Inhibition of pain responses by activation of CB(2) cannabinoid receptors

    Chem Phys Lipids

    (2002)
  • A.G. Nackley et al.

    Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation

    Neuroscience

    (2003)
  • A. Dogrul et al.

    Topical cannabinoid antinociception: synergy with spinal sites

    Pain

    (2003)
  • O. Yesilyurt et al.

    Topical cannabinoid enhances topical morphine antinociception

    Pain

    (2003)
  • J.D. Richardson et al.

    Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors

    Pain

    (1998)
  • H.C. Ellington et al.

    The effect of cannabinoids on capsaicin-evoked calcitonin gene-related peptide (CGRP) release from the isolated paw skin of diabetic and non-diabetic rats

    Neuropharmacology

    (2002)
  • C. Weidner et al.

    Acute effects of substance P and calcitonin gene-related peptide in human skin – a microdialysis study

    J Invest Dermatol

    (2000)
  • M. Schmelz et al.

    Plasma extravasation and neuropeptide release in human skin as measured by intradermal microdialysis

    Neurosci Lett

    (1997)
  • G.W. Neff et al.

    Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease

    Am J Gastroenterol

    (2002)
  • L.J. Kehl et al.

    A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain

    Pain

    (2003)
  • S.J. Carlisle et al.

    Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation

    Int Immunopharmacol

    (2002)
  • C. Leterrier et al.

    Constitutive endocytic cycle of the CB1 cannabinoid receptor

    J Biol Chem

    (2004)
  • W.A. Devane et al.

    Determination and characterization of a cannabinoid receptor in rat brain

    Mol Pharmacol

    (1988)
  • L.A. Matsuda et al.

    Structure of a cannabinoid receptor and functional expression of the cloned cDNA

    Nature

    (1990)
  • V. Di Marzo et al.

    Cannabimimetic fatty acid derivatives: the anandamide family and other endocannabinoids

    Curr Med Chem

    (1999)
  • J. Harris et al.

    Spinal anandamide inhibits nociceptive transmission via cannabinoid receptor activation in vivo

    NeuroReport

    (2000)
  • E.A. Stein et al.

    Physiological and behavioural effects of the endogenous cannabinoid, arachidonylethanolamide (anandamide), in the rat

    Br J Pharmacol

    (1996)
  • P.B. Smith et al.

    The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice

    J Pharmacol Exp Ther

    (1994)
  • P.M. Zygmunt et al.

    Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide

    Nature

    (1999)
  • S.E. Jordt et al.

    Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1

    Nature

    (2004)
  • I.B. Adams et al.

    Assessment of anandamide interaction with the cannabinoid brain receptor: SR 141716A antagonism studies in mice and autoradiographic analysis of receptor binding in rat brain

    J Pharmacol Exp Ther

    (1998)
  • V. Di Marzo et al.

    Levels, metabolism, and pharmacological activity of anandamide in CB(1) cannabinoid receptor knockout mice: evidence for non-CB(1), non-CB(2) receptor-mediated actions of anandamide in mouse brain

    J Neurochem

    (2000)
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