Hemopressin, an inverse agonist of cannabinoid receptors, inhibits neuropathic pain in rats

Abstract

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 Ca2+-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.

Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla

“…Although several papers now show pharmacological effects of hemopressin in mice, noteworthy without control over its bioavailability, (e.g. Toniolo et al, 2014;Dodd et al, 2013), it appears that hemopressin is not endogenously generated but its presence being the result of a hot extraction artefact derived from longer peptides (Gelman et al, 2010;Bauer et al, 2012). Furthermore, it seems that RVD-hemopressin (pepcan-12) is the major peptide endocannabinoid species found endogenously in the CNS and in the periphery (Bauer et al, 2012;Gelman et al, 2013).…”

Analgesic tolerance and cross-tolerance to the cannabinoid receptors ligands hemopressin, VD-hemopressin(α) and WIN55,212-2 at the supraspinal level in mice

“…In fact, hemopressin has been shown to modulate nociceptive effects via complex mechanisms and to cause different pain modulations due to the differences of nociceptive assay models and injection sites [7,18]. Hemopressin has been shown to attenuate carrageenaninduced mechanical allodynia when administered by intrathecal, intraplantar and oral routes, and to inhibit neuropathic pain using chronic constriction injury model when administered by oral route [1,19]. Systemic injection of hemopressin also produced marked antinociceptive potency in the acetic acid-induced visceral nociception model [1].…”

Cannabinoids and Pain: Sites and Mechanisms of Action

“…is effective in mitigating mechanical allodynia in the CCI model (Lim, Sung, Ji, & Mao, 2003) while Costa et al (Barbara Costa et al, 2005) demonstrated that systemic administration of a CB1R antagonist significantly reduces mechanical and thermal hyperalgesia in CCI rats and in mice. Others (Toniolo et al, 2014) (Ueda et al, 2014) have also suggested that CB1R expression and activation can be maladaptive. Very recent research indicates that CB1R expression contributes to the development of persistent mechanical hypersensitivity, protects against the development of cold allodynia but is not involved in motor impairment following spared-nerve injury in mice (Sideris et al, 2016).…”