Michael M. Morgan

GABAergic modulation of the analgesic effects of morphine microinjected in the ventral periaqueductal gray matter of the rat

The possibility that GABAergic neurons in the ventral periaqueductal gray matter modulate the analgesic effects of morphine microinjected into this brain area was investigated in the rat. Microinjection of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin 3-ol (THIP) (0.4 microgram in 0.2 microliter), a GABA agonist, in the ventral periaqueductal gray matter significantly reversed the increase of tail-flick latency induced by a prior injection of morphine sulfate (4 micrograms in 0.2 microliter) at the same site. Conversely, microinjection in the same region of picrotoxin (10 ng in 0.2 microliter), a GABA antagonist, significantly potentiated the analgesic effect of the same dose of morphine. These results suggest the existence of GABAergic neurons that tonically inhibit periaqueductal gray output neurons involved in centrifugal pain inhibition. The analgesic effects of opiates may, at least in part, result from disinhibition of these GABAergic neurons.

Stimulation of the periaqueductal gray matter inhibits nociception at the supraspinal as well as spinal level

Stimulation of the periaqueductal gray matter (PAG) is known to modulate nociception at the spinal level. Several studies have suggested that nociception may also be modulated via ascending projections from the PAG. To study this hypothesis, the descending pathway was selectively disrupted immediately caudal to the PAG in 28 rats. Twenty-eight additional rats served as non-lesioned controls. All animals were chronically implanted with a stimulating electrode in the PAG, and antinociception was assessed using tests involving spinally and supraspinally mediated responses (tail-flick and hot-plate tests, respectively). Significantly fewer lesioned than non-lesioned rats showed stimulation-produced analgesia (SPA) in the tail-flick test (4 of 28 vs 14 of 28, respectively). In contrast, no significant difference in the incidence of SPA occurred between lesioned and non-lesioned rats in the hot-plate test. These findings demonstrate that nociception can be modulated at the supraspinal, as well as spinal, level.

Chronic nicotine and withdrawal effects on body weight and food and water consumption in female rats.

Female rats were used to examine the effects of chronic nicotine administration and withdrawal on food and water consumption and body weight. Rats with chronic nicotine pellet implants consumed significantly less food and water than controls for the first five days and then gradually returned to control levels of consumption. The lowest level of body weight was reached on day 9 after which there was a slow return to control weights by day 21. When the nicotine pellets were removed from the short-term exposure group on day 14, they showed significant hyperphagia and hyperdipsia and a very rapid weight gain for the next several days, which clearly outpaced the recovery of weight in the long-term nicotine exposure group. These results show that in female rats changes in weight during chronic nicotine administration and withdrawal are accompanied by changes in rates of consumption. In addition, nicotine withdrawal can cause hyperphagia and hyperdipsia even though levels of consumption had previously returned to control levels and even though the route of nicotine administration was not oral.

PERIAQUEDUCTAL GRAY STIMULATION PRODUCES A SPINALLY MEDIATED, OPIOID ANTINOCICEPTION FOR THE INFLAMED HINDPAW OF THE RAT

The objective of the present study was to characterize stimulation-produced antinociception from the periaqueductal gray matter (PAG) in rats with unilateral hindlimb inflammation induced by an intraplantar injection of Freunds complete adjuvant. Rats were chronically implanted with a bipolar stimulating electrode in the PAG. Nociception was assessed using a paw pressure test. Prior to inflammation, PAG stimulation significantly increased paw pressure threshold in both paws compared to non-stimulated controls. Following inflammation, PAG stimulation inhibited nociception in the inflamed, but not the non-inflamed paw. Systemic administration of naloxone blocked antinociception from ventral, but not dorsal PAG stimulation sites. Intrathecal, but not subcutaneous, administration of quaternary naltrexone completely blocked stimulation-produced antinociception from the PAG. The known increased levels of endogenous opioids occurring in the spinal cord ipsilateral to the site of inflammation suggest a mechanism for the selective antinociceptive effect of ventral PAG stimulation seen for the inflamed paw.

Barbiturate-induced inhibition of a spinal nociceptive reflex: role of GABA mechanisms and descending modulation.

The present study investigated the effect of systemically administered pentobarbital on the tail-flick (TF) reflex in rats, the neurochemical mechanism of action and the role of descending influences. Pentobarbital produced a clear inhibition of the TF response. Systemic administration of naloxone did not significantly alter this effect, thus it appears to be independent of endogenous opioid systems. Complete spinal transection resulted in a marked potentiation of pentobarbital-induced TF inhibition, demonstrating a spinal locus of action. Moreover, this observation suggests the existence of a tonic descending excitatory influence, opposing the pentobarbital-produced depression of nociceptive transmission in the intact animal. Intrathecal administration of pentobarbital caused a much more pronounced TF inhibition in transected than in intact animals, lending further support to this hypothesis. To identify the neurochemical mechanisms involved in pentobarbital-produced antinociception, the gamma-aminobutyric acid (GABA) antagonists bicuculline and picrotoxinin were administered intrathecally in spinalized animals. Both substances caused an attenuation of the pentobarbital effect, demonstrating the involvement of GABAergic transmission. The proposed descending excitatory system may act either presynaptically and cause a decreased release of GABA into the synapse or postsynaptically via endogenous GABA antagonistic neurotransmitters, which may change the conformation of the GABA-barbiturate receptor complex.

Site specificity in the development of tolerance to stimulation-produced analgesia from the periaqueductal gray matter of the rat

Pentobarbital-anesthetized rats were subjected to 21 min of continuous electrical stimulation of the caudal periaqueductal gray matter (PAG) at the current threshold for analgesia. Stimulation at ventral PAG sites supported analgesia for only 1 or 2 min in most animals. Stimulation at more dorsal PAG sites supported analgesia for the entire 21 min of stimulation. This demonstration of acute tolerance with continuous ventral, but not more dorsal, PAG stimulation corresponds well with previous evidence suggesting opioid mediation of analgesia from this brain region.

Contrasting effects of centromedial and basolateral amygdaloid lesions on stress-related responses in the rat

The effects of lesions in the centromedial and basolateral amygdala were examined using three different tests sensitive to the following stress-related responses: exploratory behavior, pain reactivity, and immune responses. The most clear-cut results were found with exploratory behavior. Rats with lesions of the centromedial amygdala tended to explore a radial-arm maze more quickly and entered more novel arms of the maze than controls. Those with lesions of the basolateral amygdala were generally too hesitant to explore at all. No significant differences were found between groups on measurements of natural killer cell activity. In tests of pain perception, rats in the control group displayed an analgesic response on the hot plate following an injection of the anxiogenic drug, RO 15-1788, whereas rats with centromedial lesions tended to exhibit a blunted response. These findings provide modest support for the view that the central and lateral regions of the amygdala play complementary roles in aversively motivated behaviors and in stress-related response patterns.

Characterization of stimulation-produced analgesia from the nucleus tractus solitarius in the rat

Electrical stimulation of the commissural region of the nucleus tractus solitarius (NTS) inhibits the tail-flick reflex evoked by noxious heat. This antinociception can be measured in the awake or pentobarbital anesthetized rat at current intensities that do not induce overt behavioral side effects. Glutamate microinjections into the NTS, but not immediately surrounding the NTS, also inhibit the tail-flick reflex, demonstrating that activation of NTS cell bodies, and not fibers of passage, mediates antinociception from this region. In contrast, morphine microinjections into the NTS have no effect on the tail-flick reflex in anesthetized rats. These findings provide further evidence that the NTS is involved in the modulation of nociception.

Diazepam dissociates the analgesic and aversive effects of periaqueductal gray stimulation in the rat

Electrical stimulation of the periaqueductal gray matter (PAG) of the rat can produce both analgesia and aversive reactions. To determine if these two effects can be dissociated, diazepam, a benzodiazepine, was administered to rats chronically implanted with electrodes in the PAG. The threshold for stimulation-produced analgesia or aversion, whichever was lowest, was determined before and after drug administration. Diazepam (1 mg/kg) attenuated stimulation-produced aversive reactions at 12 of 20 stimulation sites, allowing analgesia to be measured at the same threshold. Diazepam did not alter baseline pain sensitivity or thresholds for stimulation-produced analgesia. These results indicate that aversive reactions and analgesia from PAG stimulation can be pharmacologically dissociated.

Different effects of chronic nicotine treatment regimens on body weight and tolerance in the rat.

The effect of different chronic nicotine administration regimens on body weight and the development of tolerance was examined in female rats. Groups of animals were either treated with nicotine via a subcutaneous continuous release pellet or via two injections each day of either a high (5.6 mg/kg) or low (0.8 mg/kg) dose. Both the Pellet and Low injection groups showed a progressive weight loss during nicotine treatment followed by a weight gain upon cessation of treatment, but the time course and size of these weight changes were quite distinct. In contrast, the High injection group gained weight during the 17 days of nicotine treatment. Tolerance, as measured by locomotor activity following an acute injection of nicotine 1 week after cessation of chronic nicotine treatment, was evident only in the Low injection group. This study demonstrates that the regimen in which nicotine is administered is an important factor in determining the behavioral effects produced by chronic nicotine treatment.