Articles

Sexual Medicine

Localization and Function of Cannabinoid Receptors in the Corpus Cavernosum: Basis for Modulation of Nitric Oxide Synthase Nerve Activity

By: Christian Gratzkea b c, George J. Christc, Christian G. Stiefb, Karl-Erik Anderssonc and Petter Hedlunda d lowast

European Urology, Volume 57 Issue 1, February 2010, Pages 342-349

Published online: 01 February 2010

Keywords: Anandamide, CB1, CB2, Human, Monkey, Nerve, Penis, Relaxation, TRPV1

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Abstract

Background

Anandamide, a proposed endogenous cannabinoid (CB) agonist, has been shown to enhance neurogenic responses in vitro of the rat corpus cavernosal tissue (CC). However, no information is available on the distribution of CB-receptors or effects by anandamide in CC from primates or humans.

Objective

To characterize the distribution of CB-receptor isoforms in the human and primate CC and to investigate the effects of anandamide on isolated CC preparations.

Design, setting, and participants

CC tissue was excised from the crura penis of six rhesus monkeys and five patients. Expression and distribution of CB1 and CB2 receptors were characterized with Western blot analyses and immunohistochemical investigations. The effects of anandamide on isolated CC preparations were analyzed during pharmacologic and nerve-mediated activation of primate tissue in aerated organ baths.

Measurements

The expression and localization of CB1 and CB2 receptors in the primate CC and effects of anandamide on nerve-mediated relaxations and pharmacologically evoked contractions.

Results and limitations

Western blot experiments revealed CB1 and CB2 receptors at expected band weights. Within and between strands of CC smooth muscle, CB1 and CB2 immunoreactivity (IR) was found in nerve fibers that also expressed IR for nitric oxide synthase (NOS) or transient receptor potential V1 (TRPV1). Neither CB1-IR nor CB2-IR nerves were colocalized with calcitonin-gene–related peptide (CGRP)-containing or tyrosine hydroxylase-containing nerves. No differences were observed between primate and human CC sections.

Anandamide (10−9 to 10−4 M) had no contractile effects on CC smooth muscle, no relaxant effects on precontracted preparations, and no effect on phenylephrine-induced contractions. However, anandamide (10μM) inhibited electrically evoked smooth-muscle relaxations (34–48%; p0.05).

Conclusions

CB1 and CB2 receptors are located on NOS-containing nerves in primate and human CC tissue. In contrast to findings in rats, anandamide antagonized nerve-mediated relaxations of the primate CC, suggesting important species differences for CB-mediated functions. The results also suggest a peripheral mechanism for cannabis-related sexual dysfunction.

Take Home Message

The endogenous cannabinoid anandamide depresses nerve-mediated relaxation responses, probably by presynaptic modulation of the activity of cannabinoid receptors on nitric oxide synthase–containing nerves. These findings suggest a mechanism for cannabis-related sexual dysfunctions.

Keywords: Anandamide, CB1, CB2, Human, Monkey, Nerve, Penis, Relaxation, TRPV1.

Footnotes

a Department of Clinical Chemistry and Pharmacology, Lund University Hospital, Lund, Sweden

b Department of Urology, Ludwig-Maximilians University Hospital, Munich, Germany

c Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston Salem, NC, USA

d Department of Clinical Pharmacology, Linköping University Hospital, Linköping, Sweden

lowast Corresponding author. Department of Clinical Pharmacology, Lund University Hospital, S-22185 Lund, Sweden. Tel. +46706844228; Fax: +46462111987.

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