Effects of Cannabinoids on Neurotransmission in the Peripheral Nervous System

Effects of cannabinoids on the sympathetic nervous system have been studied in isolated tissues and in pithed animals (Table 4). Sympathetic neurons were usually activated by electrical stimulation. Activation of CB1 receptors led to inhibition of noradrenaline and/or ATP release and, consequently, to inhibition of the effector responses in the heart, in mesenteric and renal blood vessels and in the vas deferens. Figure 5A shows that cannabinoids inhibit sympathetic neuroeffector transmission in the heart. Sympathetically mediated vasoconstriction was inhibited in many tissues of pithed rats and rabbits. Sympathetic tone is depressed during long-term A9-tetrahydrocannabinol administration in humans; the presynaptic inhibitory effect of cannabinoids on sympathetic axon endings maybe the basis of this effect.

Cannabinoids also inhibit transmitter release from cholinergic autonomic neurons (Table 4). As an example, the bradycardia elicited by vagal nerve stimulation is depressed. Figure 5B shows that cannabinoids inhibit parasympathetic neuroef-fector transmission in the heart. Electrically evoked contractions of the ileum and urinary bladder can also be inhibited by activation of CB1 receptors (Table 4).

Finally, cannabinoids inhibit the release of neuropeptides like calcitonin gene-related peptide (CGRP), substance P and somatostatin from sensory neurons (Table 4). Capsaicin or electrical stimulation was used to evoke neuropeptide release. In some ofthese studies, the endocannabinoid anandamide was used, which has a dual effect on neuropeptide release from sensory neurons. Anandamide possesses an inhibitory effect mediated via CB1 receptors at low concentrations and

Table 4. Inhibition of neuroeffector transmission in the peripheral nervous system (continuedonnextpage)

Neurotransmitter

Species

Tissue

Method

Reference(s)

Noradrenaline

Mouse

Sympathetic neurons (cell culture)

Electrically evoked [3H]noradrenaline release

Göbel et al. 2000

Noradrenaline

Rat

Vas deferens

Electrically evoked contraction

Christopoulos et al. 2001

Noradrenaline

Rat

Vas deferens, heart atrium

Electrically evoked [3H]noradrenaline release

Ishac et al. 1996

Noradrenaline, ATP

Mouse

Vas deferens

Electrically evoked contraction

Pertwee et al. 1992,2002

ATP

Mouse

Vas deferens

Electrically evoked contraction

Lay et al. 2000

Noradrenaline

Mouse

Vas deferens

Electrically evoked [3H]noradrenaline release

Trendelenburg et al. 2000; Schlicker et al. 2003

Noradrenaline

Rat

Heart

Electrically evoked cardioaccelerator response

Malinowskaetal.2001

Noradrenaline

Rabbit

Heart

Electrically evoked cardioaccelerator response

Szabo et al. 2001

Acetylcholine

Bradycardia evoked by electrical stimulation of the vagus nerve

Noradrenaline

Man

Heart atrial appendages

Electrically evoked [3H]noradrenaline release

Molderings et al. 1999

Noradrenaline

Rat

Sympathetically innervated blood vessels of many organs

Electrically evoked increase in blood pressure in pithed rats

Malinowskaetal. 1997

Noradrenaline

Rat

Sympathetically innervated tissues of many organs

Electrically evoked increase in blood pressure and plasma noradrenaline in pithed rats

Niederhoffer et al. 2003

Noradrenaline

Rabbit

Sympathetically innervated tissues of many organs

Electrically evoked increase in blood pressure and plasma noradrenaline in pithed rabbits

Niederhofferand Szabo 1999

Noradrenaline

Rat

Mesenterial vessels

Electrically evoked noradrenaline release

Ralevic and Kendall 2002

Noradrenaline

Rat

Renal arteries

K+-evoked [3H]noradrenaline release

Deutsch et al. 1997

Noradrenaline

Guinea-pig

Lung (bronchi)

Electrically evoked [3H]noradrenaline release

Vizi et al. 2001

Adrenaline

Rabbit

Adrenal medulla

Electrically evoked increase in plasma adrenaline in pithed rabbits

Niederhoffer et al. 2001

Electrically evoked adrenaline release in isolated adrenal medullary slices

Neurotransmitter

Species

Tissue

Method

Reference(s)

Acetylcholine, ATP

Mouse

Urinary bladder

Electrically evoked contraction

Pertwee and Fernando 1996

Acetylcholine,

Mouse

Colon

Electrically evoked cholinergic and NANC

Storr et al. 2004

NANC-transmitter

postsynaptic potentials

Acetylcholine

Guinea-pig

Ileum

Electrically evoked contraction, acetylcholine release, cholinergic postsynaptic potentials

Pertwee et al. 1992,1996b; Lopez-Redondo et al. 1997; Mang et al. 2001

Acetylcholine,

Guinea-pig

Ileum

Electrically evoked contraction

Izzo et al. 1998

NANC-transmitter

Acetylcholine

Man

Ileum

Electrically evoked contraction

Croci et al. 1998

Adenosine

Guinea-pig

Ileum

Electrically evoked adenosine release

Begg et al. 2002

CGRP

Rat

Primary sensory neurons (cell culture)

Basal and capsaicin-evoked CGRP release

Ahluwalia etal.2003

CGRP, substance P,

Rat

Trachea

Capsaicin-evoked CGRP,substance P

Nemeth etal.2003

somatostatin

and somatostatin release

CGRP

Rat

Hind paw skin

Capsaicin-evoked CGRP release

Richardson etal. 1998; Ellington etal. 2002

CGRP

Rat

Spinal cord slices

Electrically evoked CGRP release

Tognetto etal. 2001

CGRP, calcitonin gene-related peptide; NANC, non-adrenergic-non-cholinergic

CGRP, calcitonin gene-related peptide; NANC, non-adrenergic-non-cholinergic

Fig. 5A, B. Cannabinoids inhibit sympatheticand parasympathetic neuroeffector transmission in the heart. A Cardiac sympathetic nerves in pithed rabbits were stimulated at a frequency of 1 Hzfor 30 s. Solvent (SOL) and WIN55212-2 (WIN) were administered i.v. as indicated by the arrows. One of the WIN groups (YOH+WIN) was pretreated with the a2-adrenoceptorantagonistyohimbine(0.5mg/kg-1;i.v.)atf = -14min.Cardioaccelerator responses are given as percentages of the initial reference value (PRE). WIN inhibited the cardioaccelerator response more strongly in the presence of YOH, probably because YOH prevented concurrent inhibition by endogenous noradrenaline. B The right vagus nerve was stimulated at a frequency of 10 Hz for 5 s. SOL, WIN and CP55940 (CP) were administered i.v. as indicated by the arrows. Cardiodecelerator responses are given as percentages of the initial reference value PRE. * Significant difference from SOL (p<0.05). See Szabo etal. (2001) for details of the experiments

Fig. 5A, B. Cannabinoids inhibit sympatheticand parasympathetic neuroeffector transmission in the heart. A Cardiac sympathetic nerves in pithed rabbits were stimulated at a frequency of 1 Hzfor 30 s. Solvent (SOL) and WIN55212-2 (WIN) were administered i.v. as indicated by the arrows. One of the WIN groups (YOH+WIN) was pretreated with the a2-adrenoceptorantagonistyohimbine(0.5mg/kg-1;i.v.)atf = -14min.Cardioaccelerator responses are given as percentages of the initial reference value (PRE). WIN inhibited the cardioaccelerator response more strongly in the presence of YOH, probably because YOH prevented concurrent inhibition by endogenous noradrenaline. B The right vagus nerve was stimulated at a frequency of 10 Hz for 5 s. SOL, WIN and CP55940 (CP) were administered i.v. as indicated by the arrows. Cardiodecelerator responses are given as percentages of the initial reference value PRE. * Significant difference from SOL (p<0.05). See Szabo etal. (2001) for details of the experiments a stimulatory effect mediated via vanilloid receptors (TRPV1, transient receptor potential V1 channel) at high concentrations (Zygmunt et al. 1999; Tognetto et al. 2001; Ahluwalia et al. 2003; Nemeth et al. 2003).

The effect of cannabinoids on peripheral autonomic transmission has been extensively reviewed by Ralevic (2003).

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