Abstract
To study the influence of the central noradrenergic system on antinociceptive effects mediated by the CB1-receptor agonist methanandamide, intact rats were contrasted with rats in which noradrenergic nerves were largely destroyed shortly after birth with the neurotoxin DSP-4 [N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (50 mg/kg sc × 2, P1 and P3); zimelidine (10 mg/kg sc, 30 min pretreatment, selective serotonin reuptake inhibitor). When rats attained 10 weeks of age, monoamine and their metabolite concentrations were determined in the frontal cortex, thalamus, and spinal cord by an HPLC/ED method. Antinociceptive effects after methanandamide (10 mg/kg ip) apply were evaluated by a battery of tests. In addition, immunohistochemistry and densitometric analysis of the cannabinoid CB1 receptor in the rat brain was performed. DSP-4 lesioning was associated with a reduction in norepinephrine content of the frontal cortex (>90 %) and spinal cord (>80 %) with no changes in the thalamus. Neonatal DSP-4 treatment produced a significant reduction in the antinociceptive effect of methanandamide in the tail-immersion test, hot-plate test and writhing tests. In the paw pressure and formalin hind paw tests results were ambiguous. These findings indicate that the noradrenergic system exerts a prominent influence on analgesia acting via the cannabinoid system in brain, without directly altering CB1 receptor density in the brain.
Highlights
Cannabinoids exert palliative effects in cancer patients by stimulating appetite and by abating nausea, vomiting, and pain
To study the influence of the central noradrenergic system on antinociceptive effects mediated by the CB1-receptor agonist methanandamide, intact rats were contrasted with rats in which noradrenergic nerves were largely destroyed shortly after birth with the neurotoxin DSP-4 [N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (50 mg/kg sc 9 2, P1 and P3); zimelidine (10 mg/kg sc, 30 min pretreatment, selective serotonin reuptake inhibitor)
In the paw pressure and formalin hind paw tests results were ambiguous. These findings indicate that the noradrenergic system exerts a prominent influence on analgesia acting via the cannabinoid system in brain, without directly altering CB1 receptor density in the brain
Summary
Cannabinoids exert palliative effects in cancer patients by stimulating appetite and by abating nausea, vomiting, and pain. Cannabinoids have been licensed for clinical use as palliative treatment of chemotherapy, but increased evidence indicates a direct antiproliferative action of these drugs on several tumor cell lines, both in vitro and in animal models (Walsh et al 2003). Recent evidence suggests that the endocannabinoid system mediates stress responses and regulates emotional homeostasis, in part, by targeting noradrenergic circuits. The midbrain locus coeruleus (LC), that contains most noradrenergic neurons and projects to multiple cortical, limbic and autonomic-related brain structures, regulates arousal, Neurotox Res (2013) 23:39–48 attention, vigilance, stress, and pain (Berridge and Waterhouse 2003; Dunn et al 2004). Clinical evidence indicates a link between NE with pain modulation and opioid withdrawal syndrome. Abrupt cessation of opioid intake precipitates opioid withdrawal, which produces several aversive responses and symptoms, i.e., an abnormal increase in pain sensitivity (hyperalgesia) (Van Bockstaele et al 2008)
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