Author: Ricciardi, Carlo Alberto ; Barrett, Brentton ; de Sousa Valente, Joao ; Hendrikse, Erica Ruth ; Argunhan, Fulye ; Thapa, Dibesh ; Aubdool, Aisah Aniisah ; Kodji, Xenia ; Gnudi, Luigi ; Arkless, Kate ; Lucy Hay, Debbie ; Carlini, Emanuele ; Brain, Susan Diana

The neuropeptide CGRP (calcitonin gene-related peptide) is a potent vasodilator, with a cardioprotective role, although the precise mechanisms are unclear. Here we show the ability of endogenous and exogenous CGRP to restore blood pressure, when nitric oxide synthesis is blocked, in a model of cardiovascular disease associated with endothelial dysfunction and impaired nitric oxide production. Male wild-type and αCGRP knockout mice received L-nitro-arginine methyl ester (150 mg/kg in drinking water) to induce a sustained hypertension with evidence of cardiovascular remodeling. The hypertensive response was exacerbated in L-nitro-arginine methyl ester-treated αCGRP knockouts, indicating that endogenous αCGRP acts in a protective manner, when nitric oxide production is diminished. Exogenous CGRP rescued αCGRP knockout mice from both hypertension and cardiovascular remodeling. Further studies using a nonrecovery protocol with a CGRP receptor antagonist (BIBN4096 BS) revealed that CGRP acts via the canonical CGRP receptor (CLR [calcitonin-like receptor]/RAMP1 [receptor activity-modifying protein]); with no effect of an antagonist (AC187) of a second CGRP-responsive receptor (the amylin-1 receptor, CTR [calcitonin receptor]/RAMP1). Blood flow, in resistance vessels of the exteriorised mesentery, was investigated. Noradrenaline–induced vasoconstriction with recovery, in L-nitro-arginine methyl ester-treated wild-type mice. However, αCGRP knockout, or BIBN4096 BS-treated wild-type mice demonstrated a similar constrictor response to noradrenaline, but significantly impaired blood flow recovery. The combined findings highlight that αCGRP protects against cardiovascular dysfunction, signaling via the canonical CGRP receptor and acting when nitric oxide production is lost, such as in endothelial dysfunction associated with vascular disease. These in vivo results support the proposal that CGRP provides a novel treatment for cardiovascular disease.

01 May 2019·NeuropsychopharmacologyQ1 · MEDICINE

An amylin analogue attenuates alcohol-related behaviours in various animal models of alcohol use disorder

Q1 · MEDICINE

Article

Author: Maccioni, Paola ; Jerlhag, Elisabet ; Kalafateli, Aimilia Lydia ; Colombo, Giancarlo ; Vallöf, Daniel ; Lorrai, Irene

Recent findings have identified salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, as a potential regulator of alcohol-induced activation of the mesolimbic dopamine system and alcohol consumption. Providing that the role of amylin signalling in alcohol-related behaviours remains unknown, the present experiments investigate the effect of sCT on these behaviours and the mechanisms involved. We showed that repeated sCT administration decreased alcohol and food intake in outbred rats. Moreover, single administration of the potent amylin receptor antagonist, AC187, increased short-term alcohol intake in outbred alcohol-consuming rats, but did not affect food intake. Acute administration of sCT prevented relapse-like drinking in the "alcohol deprivation effect" model in outbred alcohol-experienced rats. Additionally, acute sCT administration reduced operant oral alcohol self-administration (under the fixed ratio 4 schedule of reinforcement) in selectively bred Sardinian alcohol-preferring rats, while it did not alter operant self-administration (under the progressive ratio schedule of reinforcement) of a highly palatable chocolate-flavoured beverage in outbred rats. Lastly, we identified differential amylin receptor expression in high compared to low alcohol-consuming rats, as reflected by decreased calcitonin receptor and increased receptor activity modifying protein 1 expression in the nucleus accumbens (NAc) of high consumers. Collectively, our data suggest that amylin signalling, especially in the NAc, may contribute to reduction of various alcohol-related behaviours.

01 Apr 2019·European Journal of Pain

Amylin, a peptide expressed by nociceptors, modulates chronic neuropathic pain

Article

Author: Castro‐Lopes, José Manuel ; Neto, Fani Lourença ; Almeida, Lígia Sofia ; Potes, Catarina Soares

AbstractBackgroundAmylin is a calcitonin gene‐related peptide family member expressed by nociceptors. Amylin's expression is down‐regulated following nerve damage, and studies suggested it affects nociception. We aimed at clarifying amylin's effects on chronic neuropathic pain and investigating its site of action.MethodsChronic neuropathic pain was induced in rats by spared nerve injury (SNI) surgery. Mechanical allodynia/hyperalgesia and cold allodynia/hyperalgesia were assessed by the von Frey, pinprick, acetone and cold plate behavioural tests, respectively. Amylin, amylin‐receptor antagonist (AC187) or vehicle solutions were delivered chronically, by a subcutaneous (SC) mini‐osmotic pump, or acutely, by SC or intrathecal (IT) injections. Cellular and fibre markers were used to detect spinal cord alterations in SNI rats after chronic amylin administration.ResultsContinuous subcutaneous amylin administration aggravated cold allodynia in SNI animals, possibly via amylin‐receptors (AmyR) in supraspinal areas. Acute intrathecal administration of amylin attenuated mechanical hyperalgesia, whereas AC187 reduced mechanical allodynia, suggesting distinct roles of endogenous amylin and of pharmacological amylin doses when targeting spinal cord amylin receptors. Chronic amylin administration promoted c‐Fos activation only in the dorsal horn neurons of SHAM animals, suggesting a distinctive role of amylin in the activation of the spinal neuronal circuitry under neuropathic and physiological conditions. ERK1/2 phosphorylation increased in the dorsal horn neurons of SNI rats chronically treated with amylin. This ERK1/2 cascade activation may be related to amylin's effect on the aggravation of cold allodynia in SNI rats.ConclusionsAmylin's nociceptive effects seem to depend on the treatment duration and route of administration by acting at different levels of the nervous system.SignificanceAmylin modulated neuropathic pain by acting at different levels of the nervous system. Whereas supraspinal areas may be involved in amylin's induced pronociception, modulation of spinal cord amylin receptors by endogenous or pharmacological amylin doses triggers both pro‐ and antinociceptive effects.

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