Dorsal Periaqueductal Gray Research Articles

Non-NMDA receptors in the PVN are involved in cardiovascular responses to noradrenaline microinjection in the dorsal PAG

Non-NMDA receptors in the PVN are involved in cardiovascular responses to noradrenaline microinjection in the dorsal PAG

Midbrain modulation of the cardiac baroreflex involves excitation of lateral parabrachial neurons in the rat

Activation of the dorsal periaqueductal gray (PAG) evokes defense-like behavior including a marked increase in sympathetic drive and resetting of baroreflex function. The goal of this study was to investigate the role of the lateral parabrachial nucleus (LPBN) in mediating dorsal PAG modulation of the arterial baroreflex. Reflex responses were elicited by electrical stimulation of the aortic depressor nerve (ADN) at 5 Hz or 15 Hz in urethane anesthetized rats ( n = 18). Electrical stimulation of the dorsal PAG at 10 Hz did not alter baseline mean arterial pressure (MAP) but did significantly attenuate baroreflex control of heart rate (HR) evoked by low frequency ADN stimulation. Alternatively, 40 Hz dorsal PAG stimulation increased baseline MAP (43 ± 3 mm Hg) and HR (33 ± 3 bpm) and attenuated baroreflex control of HR at both ADN stimulation frequencies. Reflex control of MAP was generally unchanged by dorsal PAG stimulation. Bilateral inhibition of neurons in LPBN area ( n = 6) with muscimol (0.45 nmol per side) reduced dorsal PAG-evoked increases in MAP and HR by 50 ± 4% and 95 ± 4%, respectively, and significantly reduced, but did not completely eliminate dorsal PAG attenuation of the cardiac baroreflex. Bilateral blockade of glutamate receptors in the LPBN area ( n = 6) with kynurenic acid (1.8 nmol) had a similar effect on dorsal PAG-evoked increases in MAP, HR and cardiac baroreflex function. Reflex control of MAP was unchanged with either treatment. These findings suggest that the LPBN area is one of several brainstem regions involved in descending modulation of the cardiac baroreflex function during defensive behavior.

Enhanced reactivity of 5-HT1A receptors in the rat dorsal periaqueductal gray matter after chronic treatment with fluoxetine and sertraline: Evidence from the elevated T-maze

Behavioral evidence indicates that sensitization of 5-HT1A and 5-HT2A receptors in the dorsal periaqueductal gray (DPAG) may underlie the therapeutic effect of serotonin reuptake inhibitors (SRIs) in panic disorder. These results were obtained from studies using animal models that associate escape behavior with panic attacks, such as the elevated T-maze. In this test, chronic administration of the non-selective SRI imipramine enhances the inhibitory effect on escape caused by the intra-DPAG injection of the 5-HT1A receptor agonist 8-OH-DPAT. We here evaluated the generality of this finding by investigating the effect of chronic administration of two selective SRIs (SSRIs), fluoxetine and sertraline, on the reactivity of the rat DPAG 5-HT1A receptors. The results showed that both SSRIs inhibited escape behavior in the elevated T-maze, suggestive of a panicolytic-like effect. Whereas intra-DPAG injection of a low dose of 8-OH-DPAT (0.4 nmol) had no effect on escape in control animals, it significantly enhanced the inhibitory effect caused by the SSRIs on this response. Microinjection of 8-OH-DPAT in SSRI-treated rats also inhibited the acquisition of inhibitory avoidance, another defensive response measured by the elevated T-maze. The results indicate that chronic administration of fluoxetine and sertraline sensitizes 5-HT1A receptors in the DPAG. Overall, they support the view that facilitation of 5-HT1A receptor-mediated neurotransmission in the DPAG is implicated in the therapeutic effect of SRIs on panic disorder.

Autonomic neurosurgery: from microvascular decompression to image guided stimulation

The paper reviews mechanisms underlying autonomic disorders, with a focus on cardiovascular dysfunction. Neurosurgical approaches are described for medically refractory hypertension and orthostatic hypotension. After review of microvascular decompression of the rostral ventrolateral medulla, stereotactic CT and MRI guided deep brain stimulation of the periaqueductal grey matter (PAG) is evaluated. Results are presented from patient studies showing reductions in blood pressure with ventral PAG stimulation and increases in blood pressure with dorsal PAG stimulation. A rationale for the treatment of autonomic disorders by neurosurgical intervention is discussed.

Effects of intra-PAG infusion of ovine CRF on defensive behaviors in Swiss-Webster mice

The midbrain dorsal periaqueductal gray (DPAG) is part of the brain defensive system involved in active defense reactions to threatening stimuli. Corticotrophin releasing factor (CRF) is a peptidergic neurotransmitter that has been strongly implicated in the control of both behavioral and endocrine responses to threat and stress. We investigated the effect of the nonspecific CRF receptor agonist, ovine CRF (oCRF), injected into the DPAG of mice, in two predator–stress situations, the mouse defense test battery (MDTB), and the rat exposure test (RET). In the MDTB, oCRF weakly modified defensive behaviors in mice confronted by the predator (rat); e.g. it increased avoidance distance when the rat was approached and escape attempts (jump escapes) in forced contact. In the RET, drug infusion enhanced duration in the chamber while reduced tunnel and surface time, and reduced contact with the screen which divides the subject and the predator. oCRF also reduced both frequency and duration of risk assessment (stretch attend posture: SAP) in the tunnel and tended to increase freezing. These findings suggest that patterns of defensiveness in response to low intensity threat (RET) are more sensitive to intra-DPAG oCRF than those triggered by high intensity threats (MDTB). Our data indicate that CRF systems may be functionally involved in unconditioned defenses to a predator, consonant with a role for DPAG CRF systems in the regulation of emotionality.

Reversible inactivation of the dorsal raphe nucleus blocked the antipanic-like effect of chronic imipramine in the elevated T-maze

Antidepressant drugs are effective in the treatment of panic in human panic disorder patients. One hypothesis is that the anti-panic effects of antidepressant drugs are mediated by an increase in the activity of serotonergic neurons within dorsal raphe nucleus (DRN) leading to an increase in serotonin-mediated inhibition of the dorsal periaqueductal gray (DPAG). In order to test this hypothesis, we investigated the effects of reversible inhibition of the DRN on behavior in the elevated T-maze (ETM) in control rats and rats chronically treated with imipramine. Rats were injected daily with imipramine (15mg/kg i.p.) or saline for 24 days. A guide cannula was implanted in the DRN on day 14. Lidocaine (4%, 0.2μL) or saline was injected into the DRN 10min before the test in the ETM followed immediately by the open-field test (day 21). Three days later, the infusions were crossed-over, rats microinjected into the DRN with saline in the first trial received lidocaine and vice versa, and the behavioral tests were repeated (day 24). Chronic saline plus lidocaine in the DRN and chronic imipramine (plus saline or lidocaine in the DRN) impaired inhibitory avoidance, indicating an anxiolytic effect. In the one-way escape, lidocaine facilitated it, suggesting a panicogenic effect, while chronic imipramine impaired it, which is indicative of a panicolytic effect. Moreover, lidocaine blocked the facilitatory effect of chronic imipramine. The locomotor activity in the open field was not changed by any treatment compared to the control group. These effects were congruent with the hypothesis that the DRN has a dual effect on anxiety: increasing learned anxiety and decreasing innate anxiety. Moreover, they suggest that the DRN exerts a crucial role in the antipanic-like effect of chronic imipramine in the ETM.

Physical environment modulates the behavioral responses induced by chemical stimulation of dorsal periaqueductal gray in mice

In order to investigate the relationship between behaviors elicited by chemical stimulation of the dorsal periaqueductal gray (dorsal PAG) and spontaneous defensive behaviors to a predator, the excitatory amino acid d, l-homocysteic acid (5 nmol in 0.1 μl), was infused into the dorsal PAG and behavioral responses of mice were evaluated in two different situations, a rectangular novel chamber or the Mouse Defense Test Battery (MDTB) apparatus. During a 1-min period following drug infusion, more jumps were made in the chamber than in the MDTB runway but running time and distance traveled were significantly higher in the runway. Animals were subsequently tested using the standard MDTB procedure (anti-predator avoidance, chase and defensive threat/attack). No drug effects on these measures were significant. In a further test in the MDTB apparatus, the pathway of the mouse during peak locomotion response was blocked 3 times by the predator stimulus (anesthetized rat) to determine if the mouse would avoid contact. Ninety percent of d, l-homocysteic treated animals made direct contact with the stimulus (rat), indicating that d, l-homocysteic-induced running is not guided by relevant (here, threat) stimuli. These results indicate that running as opposed to jumping is the primary response in mice injected with d, l-homocysteic into the dorsal PAG when the environment enables flight. However, the lack of responsivity to the predator during peak locomotion suggests that d, l-homocysteic-stimulation into the dorsal PAG does not induce normal antipredator flight.

Rostrocaudal somatotopy in the neural connections between the lateral hypothalamus and the dorsal periaqueductal gray of the rat brain.

1. The lateral hypothalamus (LH) and the dorsal periaqueductal gray area (dPAG) are two important brain structures involved in central cardiovascular control. 2. In the present study, we searched for possible rostrocaudal somatotopy in the neural connections from the three subdivisions of the LH (anterior-LHa; tuberal-LHt and posterior-LHp) to the different rostrocaudal portions of the dPAG. 3. The bidirectional neuronal tracer biotinylated-dextran-amine (BDA) was microinjected into different rostrocaudal coordinates of the dPAG (AP 3.4-2.7 mm) of male Wistar rats. One week later, animals were sacrificed and brain slices were processed and analyzed to detect neuronal efferent projections from the LH to the dPAG. 4. Neuronal cell body staining was observed along all the rostrocaudal axis of the LH when BDA was microinjected in more rostral dPAG coordinates. When the BDA was microinjected into more caudal dPAG regions, labeled neurons were observed only in the caudal portion of the LH. 5. Efferent projections from the LHa were directed only to the rostral portion of the dPAG. Projections from the rostral and medial portions of the LHt were also directed to the rostral dPAG, whereas both rostral and caudal dPAG received projections from the caudal portion of the LHt. Efferent projections from the anterior portion of the LHp were directed to both rostral and caudal dPAG, whereas projections from the caudal LHp were only directed to the rostral portion of the dPAG.6. The results suggest a somatotopic correlation in LH projections to the dPAG with main connections to the rostral dPAG, which are efferent from the three divisions of the LH. More caudal regions of the dPAG received afferents only from posterior sites in the LH. 7. Moreover, the results point out to extensive and complex neural somatotopic projections from all LH subdivisions to different rostrocaudal portions of the dPAG, reinforcing the idea of significant functional interactions between the brain structures.

Efeito ansiolítico da espermina microinjetada na substância cinzenta periaquedutal dorsal de ratos

To investigate a possible effect of the spermine and its polyamins receptors in the dorsal periaqueductal grey (DPAG) in anxiety. Groups of rats received microinjections of spermine (2.5 nmol) into DPAG and were tested in the elevated plus-maze apparatus. Results indicated an overall significant increase in the percentage of entries and in the time spent in open arms. In another experiment the anxiolytic effect obtained after the microinjection of spermine (2.5 nmol) into DPAG was block by previous microinjection of polyamines antagonists, arcaine (4 nmol) or ifenprodil (5 nmol) into the same site. These results indicate that the spermine receptor interaction in the modulation of anxiety in rats exposed to the elevated plus-maze. Considering that polyamines are natural component of the brain, these results suggest that polyamine system within DPAG may play a role in aversion and anxiety

Plus-maze following the microinjection of muscimol into the dorsal periaqueductal gray of the rat

Plus-maze following the microinjection of muscimol into the dorsal periaqueductal gray of the rat

P.4.b.004 Stimulation of the lateral habenula inhibits a panic-like behaviour by activation of serotonin-1A receptors in the rat dorsal periaqueductal gray

The transient receptors potential vanilloid type 1 channels (TRPV1) are expressed in several brain regions related to defensive behaviors, including the dorsolateral periaqueductal gray (dlPAG). The endocannabinoid anandamide, in addition to its agonist activity at cannabinoid type 1 (CB1), is also proposed as an endogenous agonist of these receptors, through which it could facilitate anxiety-like responses. The aim of this work was to test the hypothesis that TRPV1 in the dlPAG of rats would mediate panic-like responses in two models, namely the escape responses induced by chemical stimulation of this structure or by exposure to the elevated T-Maze (ETM). Antagonism of TRPV1 with capsazepine injected into the dlPAG reduced the defense response induced by local NMDA-injection, suggesting an anti-aversive effect. In the ETM, capsazepine inhibited escape response, suggesting a panicolytic-like effect. Interestingly, this effect was prevented by a CB1 antagonist (AM251). The present study showed that antagonism of TRPV1 in the dlPAG induces panicolytic-like effects, which can be prevented by a CB1 antagonist. Therefore, these antiaversive effects of TRPV1 blockade may ultimately occur due to a predominant action of anandamide through CB1 receptors.

Effects of fluoxetine and buspirone on the panicolytic-like response induced by the activation of 5-HT1A and 5-HT2A receptors in the rat dorsal periaqueductal gray

Administration of 5-hydroxytryptamine (5-HT)1A and 5-HT2A receptor agonists into the dorsal periaqueductal gray (DPAG) inhibits escape, a defensive behavior associated with panic attacks. Long-term treatment with the antipanic compound imipramine enhances the DPAG 5-HT1A- and 5-HT2A-receptor-mediated inhibition of escape, implicating these receptors in the mode of action of panicolytic drugs. In the present study, we investigated whether the inhibitory effect on escape elicited by the intra-DPAG injection of 5-HT1A and 5-HT2A receptor agonists is also enhanced after treatment with fluoxetine, another widely used antipanic drug. The effects of fluoxetine were compared to those of buspirone, an anxiolytic drug without major effect on panic disorder. Male Wistar rats, subchronically (3-6 days) or chronically (21-24 days) treated with fluoxetine (10 mg/kg i.p.) or chronically treated with buspirone (0.3 mg/kg i.p.), were intra-DPAG injected with 5-HT (20 nmol), the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT; 8 nmol) or the preferential 5-HT2A receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl) piperazine dihydrochloride (DOI; 16 nmol). The intensity of electrical current that applied to the DPAG-evoked escape behavior was measured before and after the microinjection of these agonists. The electrical current necessary to produce escape was increased after the microinjection of the three 5-HT receptor agonists in all groups of animals tested. However, this panicolytic-like effect was significantly higher in animals receiving long-term treatment with fluoxetine. The results suggest that facilitation of the 5-HT1A- and 5-HT2A-receptor-mediated inhibition of DPAG neuronal activity is implicated in the beneficial effect of antidepressants in panic disorder.

Potentiating role of interleukin 2 (IL-2) receptors in the midbrain periaqueductal gray (PAG) upon defensive rage behavior in the cat: Role of neurokinin NK 1 receptors

Feline defensive rage is a form of aggression occurring in nature in response to a threatening condition and is elicited under laboratory conditions by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Since it has recently been shown that cytokines can modulate neurotransmitter release, the present study was designed to determine the effects of administration of interleukin 2 (IL-2) into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of relatively low doses of IL-2 into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus. The specificity of this phenomenon was supported by the following findings: (1) IL-2 induced effects were dose- and time-dependent, (2) the facilitative effects of IL-2 could be completely blocked by pre-treatment of the injection site with either anti-IL-2 or anti-IL-2 receptor antibody and (3) IL-2 administration into the PAG showed no effect upon another form of aggression, namely predatory attack, elicited from the lateral hypothalamus. The findings further demonstrated that the effects of IL-2 were mediated by an NK 1 receptor mechanism since pre-treatment of the PAG with an NK 1 receptor antagonist completely blocked the facilitating effects of IL-2. Immunocytochemical observations supported these findings by demonstrating an extensive pattern of labeling of IL-2Rα in the dorsal PAG. The present study thus demonstrates that IL-2 in the dorsal PAG potentiates defensive rage behavior and is mediated through an NK 1 receptor mechanism.

5-HT1A and 5-HT2A receptors in the rat dorsal periaqueductal gray mediate the antipanic-like effect induced by the stimulation of serotonergic neurons in the dorsal raphe nucleus

It has been proposed that the serotonergic pathway that connects the dorsal raphe nucleus (DRN) to the dorsal periaqueductal gray (DPAG) is implicated in the regulation of escape, a behavior that has been related to panic. We further evaluated this hypothesis by investigating whether intra-DRN injection of the 5-HT(1A) receptor antagonist WAY-100635 changes the escape response of rats submitted to the elevated T-maze. This test also measures inhibitory avoidance, which has been associated with generalized anxiety disorder. We also investigated whether the 5-HT(1A) and 5-HT(2A) receptors in the DPAG mediate the behavioral consequences induced by the injection of WAY-100635 into the DRN. Intra-DRN injection of WAY-100635 facilitated inhibitory avoidance, while impairing escape. The same effect was obtained after intra-DRN injection of the glutamate receptor agonist kainic acid. Preadministration of WAY-100635 into the DPAG counteracted the effect induced by intra-DRN injection of WAY-100635 and of kainic acid on escape, but not on inhibitory avoidance. Preadministration of the preferential 5-HT(2A) receptor antagonist ketanserin into the DPAG abolished the effects of intra-DRN injection of WAY-100635 on both elevated T-maze tasks. The results are indicative that 5-HT(1A) autoreceptors in the DRN are under tonic inhibitory influence by endogenous 5-HT. The effects of 5-HT release in the DPAG after intra-DRN injection of WAY-100635 and kainic acid on inhibitory avoidance and escape involve different 5-HT receptor subtypes. Whereas 5-HT(2A) receptors in the DPAG seem to mediate the effect of 5-HT on both behaviors, 5-HT(1A) receptors are only involved in the regulation of escape.

Involvement of the periaqueductal gray in the hypotensive response evoked by l-glutamate microinjection in the lateral hypothalamus of unanesthetized rats

The lateral hypothalamus (LH) is involved in cardiovascular control. l-glutamate ( l-glu) stimulation of the LH of unanesthetized rats evoked hypotensive responses without significant heart rate changes. The neuronal pathway that mediates this response is unknown. There is evidence that the periaqueductal gray (PAG) is involved in the mediation of hypotensive responses evoked by electrical stimulation of the LH. In the present study, we attempted to verify the effect of an acute and reversible pharmacological ablation of the PAG with lidocaine or CoCl 2 on the hypotensive response caused by l-glu injection in the LH of unanesthetized rats. Microinjection of the local anesthetic lidocaine or the unspecific synaptic blocker CoCl 2 in the PAG significantly attenuated the hypotensive effects of l-glu stimulation of the LH, indicating the involvement of local synapses within the PAG in the hypotensive pathway activated by LH glutamatergic receptors. Microinjection of the neuronal tracer biotinylated dextran amine (BDA) in the PAG labeled neuronal cell bodies in the LH, indicating the existence of direct connections between these areas. In conclusion, the present results indicate that the hypotensive response evoked by l-glu stimulation of LH may involve a synaptic relay in the dorsal PAG.

Fos-like immunoreactivity in the brain associated with freezing or escape induced by inhibition of either glutamic acid decarboxylase or GABA A receptors in the dorsal periaqueductal gray

GABAergic neurons exert tonic control over the neural substrates of aversion in the dorsal periaqueductal gray (dPAG). It has been shown that electrical stimulation of this region at freezing or escape thresholds activates different neural circuits in the brain. Since electrical stimulation activates cell bodies and fibers of passage, it is necessary to use chemical stimulation that activates only post-synaptic receptors. To investigate this issue further, reduction of GABA transmission was performed with local injections of either the GABA-A receptor antagonist bicuculline or the glutamic acid decarboxylase (GAD) inhibitor semicarbazide into the dorsolateral periaqueductal gray (dlPAG). Local infusions of semicarbazide (5.0 μg/0.2 μl) or bicuculline (40 ng/0.2 μl) into this region caused freezing and escape, respectively. The results obtained showed that freezing behavior induced by semicarbazide was associated with an increase in Fos expression in the laterodorsal nucleus of the thalamus (LD) and ventrolateral periaqueductal gray (vlPAG), while bicuculline-induced escape was related to widespread increase in Fos labeling, notably in the columns of the periaqueductal gray, hypothalamus nuclei, the central amygdaloid nucleus (Ce), the LD, the cuneiform nucleus (CnF) and the locus coeruleus (LC). Thus, the present data support the notion that freezing and escape behaviors induced by GABA blockade in the dlPAG are neurally segregated: freezing activates only structures that are mainly involved in sensory processing, and bicuculline-induced escape activates structures involved in both sensory processing and motor output of defensive behavior. Therefore, the freezing elicited by activation of dlPAG appears to be related to the acquisition of aversive information, whereas most brain structures involved in the defense reaction are recruited during escape.

Panicolytic-like effect induced by the stimulation of GABAA and GABAB receptors in the dorsal periaqueductal grey of rats

Activation of GABAA and benzodiazepine receptors within the dorsal periaqueductal grey inhibits the escape behaviour evoked by the electrical stimulation of this midbrain area, a defensive reaction that has been related to panic. Nevertheless, there is no evidence indicating whether the same antiaversive effect is also observed in escape responses evoked by species-specific threatening stimuli. In the present study, male Wistar rats were injected intra-dorsal periaqueductal grey with the benzodiazepine receptor agonist midazolam (10, 20 and 40 nmol), the GABAA receptor agonist muscimol (2, 4 and 8 nmol), the GABAB receptor agonist baclofen (2, 4 and 8 nmol), or with the benzodiazepine inverse agonist FG 7142 (20, 40 and 80 pmol) and tested in an ethologically-based animal model of anxiety, the elevated T-maze. Besides escape, this test also allows the measurement of inhibitory avoidance which has been related to generalised anxiety disorder. Midazolam, muscimol and baclofen impaired escape, a panicolytic-like effect, without altering inhibitory avoidance. FG 7142, on the other hand, facilitated both avoidance and escape reactions, suggesting an anxiogenic and panicogenic-like effect, respectively. The data suggest that GABAA/benzodiazepine and GABAB receptors within the dorsal periaqueductal grey are involved in the control of escape behaviour and that a failure in this regulatory mechanism may be of importance in panic disorder.

Neural segregation of Fos-protein distribution in the brain following freezing and escape behaviors induced by injections of either glutamate or NMDA into the dorsal periaqueductal gray of rats

Freezing and escape responses induced by gradual increases in the intensity of the electrical current applied to dorsal regions of the periaqueductal gray (dPAG) cause a distinct pattern of Fos distribution in the brain. From these studies, it has been suggested that a pathway involving the dPAG itself, dorsomedial hypothalamus and the cuneiform nucleus (CnF) would mediate responses to immediate danger and another one involving the amygdala and ventrolateral periaqueductal gray (vlPAG) would mediate cue-elicited responses. As electrical stimulation activates body cells and fibers of passage the need of studies with chemical stimulation of only post-synaptic fibers of the dPAG is obvious. To examine further this issue we measured Fos protein expression in brain areas activated by stimulation of the dPAG with glutamate (5 nmol/0.2 μL) and N-methyl- d-aspartate (NMDA) at doses that provoke either freezing (4 nmol/0.2 μL) or escape (7 nmol/0.2 μL) responses, respectively. The results showed that glutamate-induced freezing caused a selective increase in Fos expression in the superior and inferior colliculi as well as in the laterodorsal nucleus of the thalamus. On the other hand, NMDA-induced escape led to widespread increases in Fos labeling in almost all structures studied. Differently from glutamate, NMDA at doses provoking freezing caused significant increase of Fos labeling in the dPAG and CnF. Therefore, the present data support the notion that freezing behavior induced by activation of either non-NMDA or NMDA receptors in the dorsolateral periaqueductal gray (dlPAG) is neurally segregated: glutamate activates only structures that are mainly involved in the sensorial processing and NMDA-induced freezing structures involved in the motor output of defensive behavior. Therefore, the freezing elicited by the activation of non-NMDA receptors seem to be related to the acquisition of aversive information, whereas that resulting from the activation of NMDA receptors could serve as a preparatory response for flight.

P.3.012 intra-dorsal raphe nucleus injection of the5-HT1 receptor antagonist WAY-100635 bits the panic-like behavior induced by chemical stimulation of the dorsal periaqueductal gray

P.3.012 intra-dorsal raphe nucleus injection of the5-HT1 receptor antagonist WAY-100635 bits the panic-like behavior induced by chemical stimulation of the dorsal periaqueductal gray

P.3.011 Correlation of HAM-A and PARS in pediatric generalized anxiety disorder

The analgesic potential of cannabinoids may be hampered by their ability to produce aversive emotion when administered systemically. We investigated the hypothesis that the midbrain periaqueductal grey (PAG) is a common substrate mediating the anti-nociceptive and potential aversive effects of cannabinoids. The rat formalin test was used to model nociceptive behaviour. Intra-PAG microinjection of the excitatory amino acid d,l-homocysteic acid (DLH) was used to induce an aversive, panic-like reaction characteristic of the defensive “fight or flight” response. Administration of the cannabinoid receptor agonist HU210 (5 μg/rat) into the dorsal PAG significantly reduced the second phase of formalin-evoked nociceptive behaviour, an effect which was blocked by co-administration of the CB1 receptor antagonist SR141716A (50 μg/rat). This anti-nociceptive effect was accompanied by an HU210-induced attenuation of the formalin-evoked increase in Fos protein expression in the caudal lateral PAG. Intra-dorsal PAG administration of HU210 (0.1, 1 or 5 μg/rat) significantly reduced the aversive DLH-induced explosive locomotor response. The anti-nociceptive effect of HU210 is likely to result from activation of the descending inhibitory pain pathway. Mechanisms mediating the anti-aversive effects of cannabinoids in the PAG remain to be elucidated. These data implicate a role for the PAG in both cannabinoid-mediated anti-nociceptive and anti-aversive responses.