Relation between injury of the periaqueductal gray and central pain in patients with mild traumatic brain injury: Observational study.

The periaqueductal gray (PAG) plays a pivotal role in pain modulation. We attempted to examine the relation between injury of the PAG and central pain in patients with mild traumatic brain injury (TBI).Sixty-one patients with mild TBI with central pain and 31 healthy control subjects were recruited for this study. Visual analog scale (VAS) was used for evaluation of central pain. The region of interest was defined for the PAG and the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were measured.The FA value was significantly lower in the patient group than in the control group (P < 0.05). However, no significant difference in the ADC value was observed between the patient and control groups (P > 0.05). VAS score of the patient group showed significant moderate negative correlation with the FA (r = -0.38), while no significant correlation was observed between VAS score and the ADC value (P < 0.05).We demonstrated injury of the PAG in patients with central pain following mild TBI and the degree of injury of the PAG was closely related to the degree of central pain.

Roles of the periaqueductal gray in descending facilitatory and inhibitory controls of intramuscular hypertonic saline induced muscle nociception.

Despite the importance of the periaqueductal gray (PAG) in the modulation of nociception and pain, many aspects of the roles of the different columns of the PAG in descending controls: facilitation and inhibition, are not understood. Employing a tonic muscle pain model established by i.m. injection of 5.8% saline into the gastrocnemius muscle, we now report the results of investigations designed to explore any differences in Fos expression in the different functional columns of the PAG in male Sprague-Dawley rats. In a second series of experiments, effects of the PAG on descending control of spinally-organized nociception were assessed by measuring hind paw withdrawal reflexes to noxious mechanical and heat stimulation before and after electrolytic lesion of specific columns of the PAG. Our results show that Fos expression within different columns of the PAG increases significantly and differentially following i.m. injection of 5.8% saline. The mean number of Fos positive neurons in the dorsolateral (dl), lateral (l), dorsomedial (dm) PAG elicited by i.m. injection of 5.8% saline reached a peak at 4h with a gradual decrease over time, whereas the maximum number of Fos-positive neurons in the ventrolateral (vl) PAG was observed 8h after i.m. injection. Contralateral lesion of the dl PAG significantly depressed ipsilateral secondary mechanical hyperalgesia in intramuscularly induced (5.8% saline) nociception (P<0.05), whereas heat hypoalgesia was not affected (P>0.05). By contrast, contralateral lesion of the vl PAG completely blocked the occurrence of ipsilateral heat hypoalgesia (P<0.05), while bilateral mechanical hyperalgesia was unaffected (P>0.05). In conclusion, functions of specific columns of the PAG in the control of spinal nociceptive activities are not homogeneous. It is suggested that, in this muscle pain model, the dl PAG and vl PAG participate in descending facilitation and inhibition of nociception, respectively.

Antagonism of stimulation-produced analgesia by naloxone and N-methyl-D-aspartate: role of opioid and N-methyl-D-aspartate receptors.

The present study aims to investigate the influence of electrical stimulation of periaqueductal gray (PAG) following peripheral nerve injury and its modulation by naloxone and N-methyl-D-aspartate (NMDA). Chronic neuropathic pain was induced by chronic constriction injury of the sciatic nerve, and subsequently a cannula was implanted in the PAG area for the purpose of electrical stimulation and intra-PAG drug administration. Intra-PAG administration of morphine, ketamine, and their combination were found to elicit antinociceptive response on hot-plate test. Electrical stimulation of PAG was also observed to demonstrate decreased pain response on hot-plate test, and this effect was reversed by the administration of naloxone, NMDA, and their combination, when injected into the PAG area. These findings suggest that apart from the opioid receptors, probably NMDA receptors also have a role to play in stimulation-produced analgesia.

Is the periaqueductal gray an essential relay center for the micturition reflex pathway in the cat?

The periaqueductal gray (PAG), especially in a region between the levels the oculomotor nucleus and the trochlear nucleus, was suggested to be the essential relay center that conveys information of bladder fullness to the pontine micturition center (Barrington's nucleus). The present study examined this hypothesis by transecting the brainstem in anesthetized cats. In eight cases of the midbrain transection, all (n=3) or most (n=5) of the PAG between the levels the oculomotor nucleus and the trochlear nucleus was separated from the intact side of the brain. Furthermore, in the former three cases, the PAG at the level caudal to the trochlear nucleus was separated from the intact brain by more than half (n=2) or completely (n=1). In all these cases, there were no remarkable differences in the amplitude of the micturition contraction (80-98% of that before transection), irrespective of the levels of the transection. In the cases of the pontine transection, micturition contraction disappeared after transecting through the caudal part of Barrington's nucleus (n=1) or through regions caudal to this nucleus (n=5). In the one case that received a transection through the rostral part of Barrington's nucleus, the amplitude of the micturition contraction was 43% of that before transection. This study demonstrates that Barrington's nucleus is essential, but the PAG is not essential, for evoking micturition. Our results suggest that the information of bladder fullness in the cat is conveyed to Barrington's nucleus either directly from the lumbosacral neurons or indirectly via relay neurons located below the midbrain.

A role for the periaqueductal gray in switching adaptive behavioral responses.

Previous studies suggested a role for the rostral lateral periaqueductal gray (PAG) in the inhibition of maternal behavior induced by low doses of morphine in dams with previous morphine experience. In the present study, we first showed that unilateral NMDA lesions placed in this particular PAG region prevented the morphine-induced inhibition of maternal behavior in previously morphine-sensitized dams. As suggested by previous Fos data on the PAG, predatory hunting appears as a likely candidate to replace maternal behavior in the morphine-treated dams. By testing saline- and morphine-treated dams with live cockroaches only, we have presently shown that morphine challenge increased insect hunting. Moreover, morphine- and saline-treated dams were also observed in an environment containing pups and roaches. Although most of the saline-treated animals displayed active nursing and only occasionally presented insect hunting, all of the morphine-treated animals ignored the pups and avidly pursued and caught the roaches. We next questioned whether the rostral lateral PAG would be involved in this behavioral switch. Our results showed that unilateral lesions of the rostral lateral PAG, but not other parts of the PAG, partially impaired predatory hunting and restored part of the maternal response. Moreover, bilateral lesions of the rostral lateral PAG produced even more dramatic effects in inhibiting insect hunting and restoring maternal behavior. The present findings indisputably show that the rostral lateral PAG influences switching from maternal to hunting behavior in morphine-treated dams, thus supporting a previously unsuspected role for the PAG in selecting adaptive behavioral responses.

Role for dopamine neurons of the rostral linear nucleus and periaqueductal gray in the rewarding and sensitizing properties of heroin.

There is a mesencephalic dopaminergic network outside the ventral tegmental area (VTA), including structures such as the rostral linear nucleus (RLi) and periaqueductal gray (PAG). These nuclei project to neural areas implicated in reinforcing effects of drugs, indicating that they could participate in opiate reward. The objectives were to study the morphological characteristics of the dopamine network of the RLi/PAG region, and to discern its role on rewarding and sensitizing effects of heroin in rats, following dopamine depletion or local injection of dopaminergic antagonists. The findings indicated that this network is composed of small cells in the RLi/ventral PAG, large multipolar dopamine PAG neurons, and periaqueductal PAG neurons. Following repeated heroin, large PAG neurons and small RLi/ventral PAG cells (not periaqueductal neurons) were activated, since tyrosine-hydroxylase was adaptively induced, without changes in protein kinase Aalpha. After dopamine depletion, small RLi/ventral PAG neurons and large cells of the PAG (not periaqueductal ones) were selectively affected by the neurotoxin. Dopamine neurons of the nearby VTA and dorsal raphe were not affected, as revealed by cell counting. After lesion, 'anxiety-like' responses and basal locomotion were not altered. However, conditioned place preference to heroin was found to be abolished, as well as heroin-induced motor sensitization. Following infusions of dopaminergic antagonists into RLi/PAG, D(2) (not D(1)) receptor blocking dose-dependently abolished heroin-induced reward. The present study provides evidence that dopamine neurons of the RLi/PAG region (excluding PAG periaqueductal cells) show adaptive biochemical changes after heroin, and mediate the rewarding and sensitizing effects of this drug. D(2) dopamine receptors within the RLi/PAG region participate in these effects.

Lesions of the periaqueductal gray block the medial preoptic area-induced activation of the urethrogenital reflex in male rats.

The medial preoptic area (MPOA) is important for male sexual behavior, including erections and ejaculation. Stimulation of the MPOA evokes urethrogenital reflex-like responses. However, the descending pathways mediating this response are unknown. We examined the effect of bilateral lesions of the periaqueductal gray (PAG) on the MPOA-induced response. Electrical stimulation of the MPOA was used to induce rhythmic motor patterns of the bulbospongiosus muscle, discrete regions of the PAG were lesioned and the response to MPOA stimulation re-examined. These studies demonstrate that the descending pathway mediating the MPOA-induced activation of the urethrogenital reflex-like responses travel through and may relay in the PAG.

Opiate anti-nociception is attenuated following lesion of large dopamine neurons of the periaqueductal grey: critical role for D1 (not D2) dopamine receptors.

The periaqueductal grey (PAG) area is involved in pain modulation as well as in opiate-induced anti-nociceptive effects. The PAG possess dopamine neurons, and it is likely that this dopaminergic network participates in anti-nociception. The objective was to further study the morphology of the PAG dopaminergic network, along with its role in nociception and opiate-induced analgesia in rats, following either dopamine depletion with the toxin 6-hydroxydopamine or local injection of dopaminergic antagonists. Nociceptive responses were studied through the tail-immersion (spinal reflex) and the hot-plate tests (integrated supraspinal response), establishing a cut-off time to further minimize animal suffering. Heroin and morphine were employed as opiates. Histological data indicated that the dopaminergic network of the PAG is composed of two types of neurons: small rounded cells, and large multipolar neurons. Following dopamine depletion of the PAG, large neurons (not small ones) were selectively affected by the toxin (61.9% dopamine cell loss, 80.7% reduction of in vitro dopaminergic peak), and opiate-induced analgesia in the hot-plate test (not the tail-immersion test) was reliably attenuated in lesioned rats (P < 0.01). After infusions of dopaminergic ligands into the PAG, D(1) (not D(2)) receptor antagonism attenuated opiate-induced analgesia in a dose-dependent manner in the hot-plate test. The present study provides evidence that large neurons of the dopaminergic network of the PAG participate in supraspinal (not spinal) nociceptive responses after opiates through the involvement of D(1) dopamine receptors. This dopaminergic system should be included as another network within the PAG involved in opiate-induced anti-nociception.

Lesions of the periaqueductal gray disrupt input to the rostral ventromedial medulla following microinjections of morphine into the medial or basolateral nuclei of the amygdala.

Microinjections of morphine into the basolateral (BLa) and medial (MEa) nuclei of the amygdala differentially affect rostral ventromedial medulla (RVM) neuronal activity and nocifensive behaviors. PAG lesions attenuated or blocked the effects of both BLa and MEa morphine on RVM cell activity, and interfered with the behavioral antinociception produced by BLa infusions. These results demonstrate that the influences from both the BLa and MEa to the RVM are relayed via the PAG.

Antipanic procedures reduce the strychnine-facilitated wild running of rats.

Wild running (WR) behavior of rats seen in response to intense acoustic stimulation of audiogenic seizure-paradigm is very similar to the panic flight and can be facilitated by subconvulsive doses of strychnine. The present work aimed to test whether antipanic procedures, such as dorsal periaqueductal gray (dPAG) lesion and imipramine treatments, affect the strychnine-facilitated WR. In study 1, six Wistar male adult rats with electrolytic lesion of dPAG had their WR completely blocked, whereas it was facilitated in 50% of sham-lesioned control rats by a dose of 0.5 mg/kg of strychnine administered intraperitoneal. This effect was not reproduced with a higher strychnine dose (1.0 mg/kg). In study 2, the effects of imipramine were investigated by testing 36 rats under a dose of strychnine that induces WR in 50% of subjects. They were assigned into three experimental groups: imipramine treatments of 5.0 and 10.0 mg/kg, and infusions of saline. All these treatments were subchronical with three intraperitoneal injections within 24 h. Imipramine (10.0 mg/kg) reduced the incidence of WR in comparison to the saline results. It is concluded that strychnine-facilitated WR is reduced by antipanic procedures and, therefore, can be viewed as a manifestation closely related to panic.

Influence of dorsolateral periaqueductal grey (dlPAG) lesions on contextual conditioning with massed and distributed shock.

Three experiments investigated the conditions under which electrolytic lesions of the dorsolateral periaqueductal grey (dlPAG) facilitate conditioned defensive freezing in the rat (Rattus norvegicus). Experiment 1 found that dlPAG lesions placed before context-shock pairings facilitated conditioned defensive freezing with massed but not distributed shock. No such effect was found in Experiment 2, when the lesions were placed after context-shock pairings. Experiment 3 found that dlPAG lesions facilitated subsequent conditioning with massed but not a single shock. In addition, no differences in sensitivity to thermal or shock pain were evident in lesioned and unlesioned rats. Taken together, these results are consistent with the suggestion that dlPAG activation interferes with the processing of contextual cues during association formation.