The neuropeptide galanin modulates behavioral and neurochemical signs of opiate withdrawal

Abstract

Much research has focused on pathways leading to opiate addiction. Pathways opposing addiction are more difficult to study but may be critical in developing interventions to combat drug dependence and withdrawal. Galanin decreases firing of locus coeruleus neurons, an effect hypothesized to decrease signs of opiate withdrawal. The current study addresses whether galanin affects morphine withdrawal signs by using a galanin agonist, galnon, that crosses the blood-brain barrier, and mice genetically engineered to under-or overexpress galanin peptide. Galnon significantly decreased morphine withdrawal signs in C57BL͞6 mice. Further, knockout mice lacking galanin showed exacerbated morphine withdrawal signs, suggesting that endogenous galanin normally counteracts opiate withdrawal. Transgenic mice overexpressing galanin in noradrenergic neurons also showed decreased morphine withdrawal signs, suggesting a possible neuroanatomical locus for these effects of galanin. Both c-fos immunoreactivity, a marker of neuronal activity, and phosphorylation of tyrosine hydroxylase at Ser-40, a marker of cAMP levels, are decreased in the locus coeruleus by galnon treatment after morphine withdrawal, suggesting a possible molecular mechanism for the behavioral effects of galanin. These studies suggest that galanin normally acts to counteract opiate withdrawal and that small molecule galanin agonists could be effective in diminishing the physical signs of withdrawal.

Orexin Mediates the Expression of Precipitated Morphine Withdrawal and Concurrent Activation of the Nucleus Accumbens Shell

“…Here, we chose an injection paradigm where animals receive morphine injections of escalating doses (47,48). This allows for better control over morphine dosing, while also reflecting escalating drug intake that is seen in addicts.…”

“…The constant assigned to each symptom, designed to reflect the severity and occurrence of a particular symptom, was adapted from previously published global score calculations for both rats (46) and mice (47,48). Jumps and paw tremors were multiplied by 0.1; gnawing, ptosis, and head swoops were multiplied by 0.5; tremors, wet dog shakes, and backward walking were multiplied by 1.0.…”

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

“…Galnon is a galanin agonist that is thought to have some selectivity for GalR1 over GalR2 and GalR3 (Saar et al, 2002;Wu et al, 2003). Galnon can act as a galanin receptor agonist in vivo in behavioral paradigms modulated by the endogenous peptide galanin, including opiate withdrawal (Zachariou et al, 2003), feeding behavior (Abramov et al, 2004), seizures (Saar et al, 2002), and anxiety (Rajarao et al, 2007). However, it should be noted that galnon can also interact directly with some G proteins (Flören et al, 2005), thus the action of galnon may not be limited to activation of GalR1.…”

“…Central infusion of galanin attenuates morphine place preference in the mouse (Zachariou et al, 1999). Further, galanin knockout (GKO) mice demonstrate increased signs of opiate withdrawal, whereas transgenic overexpression of galanin or administration of the galanin agonist galnon attenuates opiate withdrawal (Zachariou et al, 2003). These findings suggest that galanin has the potential to decrease abuse liability of opiates.…”

“…Galanin binds to G protein-coupled receptors (GPCRs) and can modulate intracellular signaling pathways that are involved in addiction (Hawes et al, 2006a, b;Nestler, 2001;Zachariou et al, 2003). All three galanin receptor subtypes, as well as significant galanin binding, are found in the ventral tegmental area (VTA), amygdala, nucleus accumbens (NAc), cingulate cortex, and locus coeruleus (LC) (Burgevin et al, 1995;Gustafson et al, 1996;Hawes and Picciotto, 2004;Kolakowski et al, 1998;Waters and Krause, 2000), areas of the brain known to contribute to drug addiction and reward.…”