Inhibition of Tuberoinfundibular Dopaminergic Neural Activity During Suckling: Involvement of μ and κ Opiate Receptor Subtypes

Abstract

Previous studies have shown that mu (mu) and kappa (kappa) opioid antagonists inhibit suckling-induced prolactin release. Prolactin responses elicited by pup suckling or opioid administration are mediated, at least in part, by suppression of dopamine (DA) release from tuberoinfundibular dopaminergic (TIDA) neurons in the hypothalamus. We examined the effects of the mu opiate receptor antagonist, beta-funaltrexamine (beta-FNA), and the kappa opiate receptor antagonist, nor-binaltorphimine (nor-BNI) on the activity of TIDA neurons in lactating rats. TIDA neuronal activity was determined by measuring DOPA accumulation in the caudate putamen (CP) and median eminence (ME). The effects of opioid antagonist treatment were determined in pup-deprived (low circulating prolactin levels) or pup-suckled rats (high circulating prolactin levels). The accumulation of 5-hydroxytryptophan (5-HTP) in the medial preoptic area (MPOA), the anterior hypothalamus (AH) and the median eminence (ME) was quantified as an index of serotonergic activity in the same animals for comparative purposes. In vehicle treated rats, suckling caused a significant and selective decrease in DOPA accumulation in the ME. beta-FNA (5 micrograms, i.c.v.) pretreatment significantly increased DOPA accumulation in the ME of pup-deprived and pup-suckled rats. beta-FNA pretreatment also prevented the suckling-induced suppression of DOPA accumulation in the ME. In contrast to the actions of beta-FNA, pretreatment with nor-BNI (8 micrograms, i.c.v.) did not significantly affect the activity of the TIDA neurons in pup-deprived or pup-suckled rats. Suckling alone did not alter 5-HTP accumulation in any of the brain regions examined, and neither opioid antagonist had appreciable effects on 5-HTP accumulation. These results demonstrate that the EOP tonically inhibit the TIDA neurons in both pup-deprived and pup-suckled, post-partum female rats by acting through the mu, but not the kappa, opiate receptor subtype. Furthermore, the suckling-induced inhibition of TIDA neurons is also mediated through the EOP acting at mu, but not kappa opioid receptors.

Evidence That Gz-Proteins Couple to Hypothalamic 5-HT1AReceptorsIn Vivo

“…Therefore, pertussis toxin-induced inactivation of G i /o -proteins coupled to the -opioid receptors in the hypothalamus could produce a disinhibition of dopaminergic neurons and result in increased release of dopamine. Increased dopamine levels in the anterior pituitary gland inhibit the secretion of prolactin, regardless of the presence of other stimuli that increase its secretion (Pilotte and Porter, 1981;Callahan et al, 1996). This explanation is consistent with the observation that pertussis toxin treatment reduced basal prolactin levels.…”

“…For example, receptors that are coupled to pertussis toxin-sensitive G i -proteins, such as -opioid receptors (Parolaro et al, 1990;Chan et al, 1995), mediate a tonic inhibition of the activity of tuberoinfundibular dopamine neurons in the hypothalamus (Callahan et al, 1996). Therefore, pertussis toxin-induced inactivation of G i /o -proteins coupled to the -opioid receptors in the hypothalamus could produce a disinhibition of dopaminergic neurons and result in increased release of dopamine.…”

Neurotransmitters Involved in the Opioid Regulation of Prolactin Secretion at the End of Pregnancy in Rats

“…Numerous observations indicate that EOP and opiate agonists suppress the activity of TIDA neurons by activation of µ- and/or ĸ-receptors [49, 50, 51, 52], thereby increasing the prolactin secretion [53, 54]. In the present study, we did not find an inverse correlation between prolactin levels and DOPAC/DA ratio after DAMGO or β-END administration.…”

Immunoneutralization of Endogenous Opioid Peptides Prevents the Suckling-Induced Prolactin Increase and the Inhibition of Tuberoinfundibular Dopaminergic Neurons

“…Similar results have been obtained using specific opiate receptor antagonists. Administration of either the µ or ĸ receptor antagonists inhibited prolactin release during suckling [19], but only the µ site seemed to mediate inhibition of hypothalamic dopaminergic neural activity [30]. Furthermore, β-endorphin stimulated prolactin secretion in both virgin and postpartum female rats and this response was antagonized by specific µ 1 [21], µ, δ and ĸ [22]sites, indicating the involvement of multiple receptor subtypes.…”

“…This response was abolished by antagonizing the µ 1 [21], µ, δ or ĸ sites [22]indicating that β-endorphin activates a pathway involving multiple receptor subtypes. In lactating female rats, antagonism of either the µ or ĸ receptor site inhibited prolactin release during suckling [19], but only the µ site seemed to mediate inhibition of hypothalamic dopaminergic neural activity [30]. Arbogast and Voogt [1]recently reported that opioidergic input was essential for normal lactation due to the effects on the TIDA neurons.…”