μ-, δ- and κ-opioid receptor populations are differentially altered in distinct areas of postmortem brains of Alzheimer’s disease patients

Abstract

The putative role of the opioid system in cognitive and memory functions prompted us to search for possible changes in the cohort of the major opioid receptors, μ, δ and κ, in Alzheimer’s disease. The present study examines alterations in opioid receptor levels by quantitative autoradiography. These experiments were carried out on coronal sections of postmortem brains from Alzheimer’s disease patients and from aged-matched, dementia-free individuals. Brain sections were labeled with the tritiated forms of μ-, δ- and κ-opioid ligands; DAMGO ([d-Ala²,N-Me-Phe⁴,Gly-ol⁵]-enkephalin), DPDPE ([d-Pen2,5]-enkephalin) and bremazocine (in the presence of μ- and δ-ligands), respectively. Nonspecific binding was determined in the presence of naloxone (10 μM). Brain areas analyzed were caudate, putamen, amygdaloid complex, hippocampal formation and various cerebral and cerebellar cortices. Image analyses of autoradiographs show, that in comparison to the same areas in control brain, statistically significant reductions in μ-opioid receptor binding occur in the subiculum and hippocampus of Alzheimer’s disease brains. Binding of δ-opioid receptors is also decreased in the amygdaloid complex and ventral putamen of Alzheimer’s disease brains. In contrast, large increases of κ-opioid receptor binding are found in the dorsal and ventral putamen as well as in the cerebellar cortex of Alzheimer’s disease brains. Levels of μ-, δ- and κ-opioid receptor binding are unaltered in the caudate, parahippocampal gyrus and occipito–temporal gyrus. These results may suggest an involvement of the endogenous opioid system in some of the multitude of effects that accompany this dementia.

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia in the geriatric population and the prevalence of this progressive brain disease almost doubles every 5 years after the age of 65, reaching 24% of people over the age of 85 years [31]. Common symptoms of AD include memory and cognitive deficits such as language and judgment impairments, difficulties with complex motor tasks, impaired interpretation of sensory stimuli, hallucination and delusion. The complex processes controlling these physiological functions reside in numerous brain regions and are associated with several neurotransmitter systems that are most likely implicated in this dementia [3], [47], [50].

A unique pattern of distribution of the individual types of opioid receptors, μ, δ, and κ, exists in the human brain [4], [18], [37], [38], [45], [46], [48], [49], [60]. While these receptors are widely distributed in gray matter, they are preferentially found in limbic and limbic-associated brain structures. These receptors play important roles in a broad range of functions and behaviors, such as nociception, pleasure and dysphoria, neuroendocrine regulation, motor control, learning and memory [33], [38], [62]. Despite a large spectrum of affected physiological actions, only a few studies have specifically examined the endogenous opioid system in postmortem human brain and its possible alteration in pathological conditions such as suicide [13], [16], [23], addiction [12], [14], [56], Parkinson’s disease [11], [52], [68], schizophrenia [53], [59] and Alzheimer’s disease [2], [15], [18], [25], [29], [30], [54].

A possible linkage between AD and the endogenous opioid system is supported by recognition of the role of the opioid system in cognitive and memory functions. In animal models showing deficits in these functions, the integrity of the septohippocampal cholinergic system is a major factor. Thus, in rodents, the acute administration of κ-opioid receptor agonists [dynorphin A-(1-13), U50488H, U69,593] was apparently beneficial in: decreasing the degree of impairment of learning and memory processes after lesioning of cholinergic basal forebrain neurons [64], reducing cholinergic drug-induced deficits [21], [22], ameliorating other models of memory dysfunctions [20], [27], [28], [41], [65] and in the enhancement of spontaneous alternation memory in Y-maze testing [66]. Under some conditions, μ- and δ-opioid receptor ligands may have effects opposite to those of κ-opioid agonists, but they are also fully involved in memory processes in rodents [26], [28], [43]. In nonhuman primates, facilitation of learning was found after low doses of an enkephalin analog [42]. In humans, results of studies on the effects of selective opioid or opiate agonists on memory function are still inconclusive [70]. In studies of the effects of naloxone administration to AD patients, initial reports of improvement of cognitive deficit [51] were not supported by later findings [17], [44], [63].

One of the characteristics of the AD brain is the presence of an over-abundance of extraneuronal deposits of β-A4 amyloid protein (senile plaques) and intraneuronal inclusions of cytoskeletal elements (neurofibrillary tangles). These pathological hallmarks are found in the neocortex, hippocampus and the amygdala, and with a lower frequency in the basal ganglia, cerebellum and other areas [1], [7], [58]. These same anatomical regions contain, in the nondemented human brain, high levels of opioid receptors [18], [32], [49]. At present, it is unknown whether, in the AD brain, there exists a preferential specificity for the development of the lesions on or near neurons containing a specific receptor or a specific neurotransmitter. Nevertheless, the overlap between the distribution of opioid receptors and the location of lesions characteristic of AD led us to investigate possible alterations of binding levels of the three opioid receptors in AD in key areas of the brain thought to be involved in the pathology of AD.