Hemopressin, an inverse agonist of cannabinoid receptors, inhibits neuropathic pain in rats.
Direct-acting cannabinoid receptor ligands are well known to reduce hyperalgesic responses after nerve injury, although their psychoactive side effects have damped enthusiasm for their therapeutic development. Hemopressin (Hp) is a nonapeptide that selectively binds CB1 cannabinoid receptors (CB1 receptors) and exerts antinociceptive action in inflammatory pain models. We investigated the effect of Hp on neuropathic pain in rats subjected to chronic constriction injury (CCI) of the sciatic nerve, and explored the mechanisms involved. Oral administration of Hp inhibits mechanical hyperalgesia of CCI-rats up to 6h. Hp treatment also decreases Egr-1 immunoreactivity (Egr-1Ir) in the superficial layer of the dorsal horn of the spinal cord of CCI rats. The antinociceptive effect of Hp seems to be independent of inhibitory descending pain pathway since methysergide (5HT1A receptor antagonist) and yohimbine (α-2 adrenergic receptor antagonist) were unable to prevent Hp antinociceptive effect. Hp decreased calcium flux on DRG neurons from CCI rats, similarly to that observed for AM251, a CB1 receptor antagonist. We also investigated the effect of Hp on potassium channels of CCI rats using UCL 1684 (a blocker of Ca(2+)-activated K(+) channels) which reversed Hp-induced antinociception. Furthermore, concomitant administration of URB-584 (FAAH inhibitor) but not JZL-184 (MAGL inhibitor) potentiates antinociceptive effect of Hp in CCI rats indicating an involvement of anadamide on HP-induced antinociception. Together, these data demonstrate that Hp displays antinociception in pain from neuropathic etiology through local effects. The release of anandamide and the opening of peripheral K(+) channels are involved in the antinociceptive effect.
Laboratory of Neuromodulation and Experimental Pain, Hospital Sírio-Libanês, São Paulo, Brazil.
Elaine F
EF
Toniolo
Laboratory of Neuromodulation and Experimental Pain, Hospital Sírio-Libanês, São Paulo, Brazil.
Estêfani T
ET
Maique
Department of Pharmacology, University of São Paulo, São Paulo, Brazil.
Wilson A
WA
Ferreira
Proteimax Biotechnology, Cotia, Brazil.
Andrea S
AS
Heimann
Department of Pharmacology, University of São Paulo, São Paulo, Brazil.
Emer S
ES
Ferro
Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, USA.
Dinah L
DL
Ramos-Ortolaza
Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, USA.
Lydia
L
Miller
Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, USA.
Lakshmi A
LA
Devi
Laboratory of Neuromodulation and Experimental Pain, Department of Anatomy, University of São Paulo, São Paulo, Brazil. Electronic address: camila.dale@usp.br.
Camila S
CS
Dale
D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000627:therapeutic use*; D002186:Cannabinoids / Q000378:metabolism; D006454:Hemoglobins / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D010446:Peptide Fragments / Q000627:therapeutic use*; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D006454:Hemoglobins; D010446:Peptide Fragments; D015221:Potassium Channels; C473218:hemopressin
CB1 cannabinoid receptors; Chronic constriction injury model; Dorsal root ganglion; Hemopressin; Hyperalgesia