The effects of diphenhydramine and SR142948A on periaqueductal gray neurons and on the interactions between the medial preoptic nucleus and the periaqueductal gray.

The midbrain periaqueductal gray contains both neurotensin type-1 and type-2 receptors. Behavioral studies have shown that the analgesic effect of neurotensin is mediated through its interaction with the type-2 receptors. These receptors specifically bind the type-1 histamine antagonist, levocabastine. Recently, it has been shown that another histamine-1 antagonist, diphenhydramine, blocks the analgesic effect of neurotensin. In addition, it has been shown that a non-peptide neurotensin antagonist, SR142948A, binds to both types of neurotensin receptors and blocks the analgesic effect of exogenously applied neurotensin. Major afferents to the periaqueductal gray arise from the medial preoptic nucleus of the hypothalamus. This region contains neurotensinergic neurons, and the expression of neurotensin mRNA in this region increases following cold-water swim stress that leads to opioid-independent analgesia. The goal of this study was to determine whether the responses of periaqueductal gray neurons to stimulation of the medial preoptic nucleus are modified by local injection of diphenhydramine and SR142948A. Because the cellular basis of the effects of diphenhydramine on periaqueductal gray neurons had not been reported, we also examined the effects of diphenhydramine on the baseline-firing rate and synaptic transmission using in vivo and in vitro methods. The results of the in vitro studies indicate that diphenhydramine concentrations above 500 nM significantly reduce the baseline firing of the periaqueductal gray neurons without a significant effect on the frequency of postsynaptic potentials. At concentrations below 100 nM, diphenhydramine has little effect on the baseline-firing rate but partially blocks the response to neurotensin. The results of the in vivo studies showed similar effects of diphenhydramine. At high concentrations it inhibited periaqueductal gray neurons, but at low concentrations it had no effect on the baseline-firing rate and it blocked the response to neurotensin and to medial preoptic nucleus stimulation. Unlike diphenhydramine, SR142948A had virtually no effect on the baseline-firing rate but blocked the response to neurotensin and to stimulation of the medial preoptic nucleus. It is concluded that: (1) SR142948A, at a dose that completely blocks the effect of exogenously applied neurotensin on periaqueductal gray neurons, has little effect on their baseline-firing rates. (2) Because of its effect on the baseline-firing rate, only low doses of diphenhydramine can be used as an antagonist of the neurotensin analgesic effect. (3) Responses of periaqueductal gray neurons to medial preoptic nucleus stimulation is, in part, mediated by a neurotensinergic network within the periaqueductal gray.

Cold water swim stress increases the expression of neurotensin mRNA in the lateral hypothalamus and medial preoptic regions of the rat brain.

Stress-induced analgesia is a well-documented phenomenon that occurs in all mammalian species. Forced cold water swim produces a type of stress-induced analgesia that is independent of mu opioid receptors. The neuropeptide neurotensin (NT) has been implicated in mu opioid-independent analgesia (MOIA), but the circuitry of this system is largely unknown. The medial preoptic area (MPO) and lateral hypothalamus (LH) are two regions that are known to modulate pain processing. These two regions also contain neurotensinergic projections to the periaqueductal gray, a region that has been shown to produce MOIA upon injection of NT. The goal of this study was to determine if cold water swim (CWS) stress, which produces MOIA, activates the NT-ergic systems in these two regions. In situ hybridization results indicate that CWS increases the level of NT mRNA within neurons in the MPO and LH, suggesting that these two regions are activated during this process.