CB2 receptor‐mediated antihyperalgesia: possible direct involvement of neural mechanisms

Abstract

In mouse the cannabinoid receptor 2 (CB2) agonists L768242 and (+)-AM1241, at doses of 30 mg/kg i.p. and 1 and 3 mg/kg i.v., respectively, reduced the second phase of nocifensive behaviors elicited by formalin intraplantar injection. This effect was counteracted by the selective CB2 antagonist SR144528 (1 mg/kg i.p.). In rat (+)-AM1241 (3 and 6 mg/kg i.v.) and L768242 (30 mg/kg i.p.) reduced allodynia elicited by L5-L6 spinal nerve ligation. SR144528 reverted these effects, supporting a CB2-mediated action. To clarify the mechanisms underlying these effects we investigated CB2 gene expression and function in the nervous system. CB2 mRNA was expressed in spinal cord and dorsal root ganglia (DRG) of both sham and neuropathic rats and was up-regulated in the ipsilateral spinal cord of neuropathic rats. Expression studies demonstrated the presence of CB2 mRNA in culture of spinal cord microglia. A biomarker, CGRP, was used to investigate modulation of DRG primary afferents by CB2 agonists. Both L768242 and (+)-AM1241 dose dependently (EC50 of 3.6 and 4.5 nM, respectively) reduced capsaicin-induced calcitonin gene-related peptide (CGRP) release. Coadministration of SR144528 resulted in a rightforward shift (pKB 8.1 and 8.2 for (+)-AM1241 and L768242, respectively) of the dose-response curve. Experiments on capsaicin-induced CGRP release in tissue from CB1-/- mice ruled out a CB1-mediated effect. These results confirm that CB2 is present in the central nervous system and suggest that CB2 agonists may elicit their analgesic effect by acting not only at non-neuronal peripheral sites but also at neural level, making CB2 an attractive target for chronic pain treatment.

Modulation of pain transmission by G-protein-coupled receptors

“…Spinal application of JWH-133 also attenuates responses of spinal dorsal neurons to mechanical stimuli in neuropathic, but not sham-operated, rats (Khasabova et al, 2004). Application of other CB2 receptor agonists, such as L768242 and AM1241, reduces capsaicin-mediated calcitonin gene-related peptide release in rat spinal cord slices (Beltramo et al, 2006). These results suggest that peripheral and spinal CB2 receptors may be an important analgesic target.…”

“…Notably, sciatic nerve injury, but not tissue inflammation, induces CB2 receptor mRNA expression in the ipsilateral dorsal horn of the spinal cord . Upregulation of CB2 receptor mRNA and proteins in the DRG and spinal cord is also found in animals subjected to spinal nerve ligation (Wotherspoon et al, 2005;Beltramo et al, 2006) or saphenous nerve ligation (Walczak et al, 2005;Walczak et al, 2006).…”

Crucial Role of CB2Cannabinoid Receptor in the Regulation of Central Immune Responses during Neuropathic Pain

“…Interestingly, the activation of CB 1 receptors expressed in peripheral nociceptors but not in the CNS attenuates neuropathic pain in rodents (Agarwal et al, 2007). The identification of CB 2 receptors in glial cells (Zhang et al, 2003;Beltramo et al, 2006) has opened new therapeutic approaches for these ligands. CB 2 receptors have been also proposed to be present in neurons (Van Sickle et al, 2005), although this issue is still controversial.…”

Analgesia adjuvante e alternativa

“…O efeito placebo é comum a todos os tratamentos, mas não é específico ao tratamento testado. Os efeitos analgésicos do placebo não se devem a inclinações pessoais ou fatores subjetivos, mas a específicos circuitos encefálicos e a processos de neurotransmissão peptidérgica relacionadas com a dor: endorfinas, encefalinas, dinorfinas e outros neurotransmissores 1,2,7-10, 21,41,42,74,164 . O efeito placebo é poderoso nas doenças de etiopatogenia psicossomática, como asma, hipertensão arterial e sín-dromes dolorosas.…”

“…The placebo effect is common to every treatment, but it is not specific to the treatment being tested. The analgesic effects of a placebo are not a consequence of personal tendencies or subjective factors, but of specific encephalic circuits and peptidergic neurotransmission connected to pain: endorphins, encephalins, dinorphins, and others 1,2,7-10, 21,41,42,74,164 . The placebo effect is very strong in diseases with a psychosomatic etiopathogeny, such as asthma, hypertension, and pain syndromes.…”