Characterization of intrathecal vasopressin-induced antinociception, scratching behavior, and motor suppression.

Intrathecal (IT) administration of vasopressin produces antinociception, scratching behavior, and motor suppression. The present experiments characterized these effects with regards to the following: 1) VP receptor specificity, 2) possible involvement of endogenous opiates, 3) possible involvement of seizure activity, and 4) whether the antinociception is due to direct actions of VP at the spinal cord. These studies showed that IT administration of a V1-specific vasopressin antagonist completely blocked the antinociception, scratching behavior, and motor suppression produced by 25 ng IT vasopressin. Furthermore, IT administration of the vasopressin metabolite, [pGlu4,Cyt6]AVP(4-9), produced none of the effects produced by vasopressin. Systemic administration of the opiate antagonists naloxone (1 mg/kg IP) and naltrexone (10 mg/kg IP) had no significant effect on the antinociception produced by IT vasopressin, whereas naltrexone potentiated the scratching behavior. Neither the IT vasopressin-induced antinociception nor scratching behavior was affected by pretreatment with the anticonvulsant sodium valproate. In addition, IT vasopressin inhibited the tail flick reflex in rats with transected spinal cords, demonstrating direct spinal effects of vasopressin. In conclusion, IT administration of vasopressin produces antinociception, scratching behavior, and motor suppression via activation of VP-specific receptors in the spinal cord.

Partial involvement of monoamines and opiates in the inhibition of rat spinal nociceptive neurons evoked by stimulation in midbrain periaqueductal gray or lateral reticular formation.

In rats anesthetized with sodium pentobarbital, we tested the effects of systemic or intrathecal administration of the opiate antagonist naloxone, the serotonergic antagonist methysergide, or the adrenergic antagonist phentolamine, on inhibition produced by electrical stimulation in midbrain periaqueductal gray (PAG) or lateral reticular formation (LRF) of the responses of single lumbar dorsal horn neurons to noxious heating (50-54 degrees C, 10 s) of hindpaw skin. Systemically administered naloxone (1-10 mg/kg i.v.) reduced (greater than 20% below predrug inhibition) inhibition from PAG and/or LRF in 5/12 units and had no effect in the remainder. Systemic methysergide (2-6 mg/kg i.v.) selectively reduced PAG-evoked inhibition in 6 units, while inhibitions from both PAG and LRF stimulation were reduced in one unit and unaffected in 8 units. Systemic phentolamine (2-4 mg/kg) reduced LRF-evoked inhibition in 4 units, while inhibitions from PAG and LRF were reduced in one unit and unaffected in 5. Intrathecally applied methysergide reduced or abolished PAG-evoked inhibition in 8/16 units and reduced or abolished LRF-evoked inhibition in 6/14 units. Reductions in the level of inhibition were reversible in one-half of the cases, whereas they persisted for over 2 h in the remainder. The mixed effects of both systemically and intrathecally administered drugs suggest that monoamines and opiates may be partly involved in spinal inhibitory mechanisms activated from the midbrain.

Electrical stimulation of the rat ventral midbrain elicits antinociception via the dorsolateral funiculus.

The pain-suppressive effects of focal electrical stimulation of sites throughout the ventral midbrain were examined in awake rats. Chronic bipolar electrodes were implanted in medial and lateral regions of the midbrain. Current thresholds for suppression of the tail-flick reflex in response to noxious heat were determined for both a biphasic and a monophasic stimulation parameter at each site. Stimulation of areas throughout the ventral midbrain produced tail-flick suppression (TFS), but no one area was consistently effective in all animals. Monophasic and biphasic stimulation were qualitatively equal in the duration of TFS and the distribution of effective sites. The production of TFS was not correlated with other behavioral reactions to brain stimulation. TFS appeared to be mediated by non-opiate pathways since naloxone administration (10 mg/kg) had no discernible effect on the production of TFS. The current threshold for producing TFS was extremely variable over both short (one half hour) and long (one week) intervals. The incidence of TFS from previously effective sites was significantly less following bilateral dorsolateral funiculus (DLF) lesions, indicating that the antinociceptive effects of ventral midbrain stimulation are mediated by this spinal pathway.

Antinociception vs motor effects of intrathecal vasopressin as measured by four pain tests.

The effects of intrathecal (i.t.) vasopressin (VP) on nociception were quantitatively tested in rats using 4 pain tests: tail flick, tail shock vocalization, hot plate, and formalin. In addition, motor effects of VP were examined qualitatively. I.t. VP produced a prolonged antinociception lasting at least 40 min on the tail flick (2.5 and 25 ng) and formalin (25 ng) tests, and a brief antinociception lasting less than 20 min on the tail shock (25 ng) and hot plate (25 ng) tests. Those rats not responding to the pain tests showed no signs of perceiving the pain stimulus, such as orientation to the stimulus or vocalization. In addition, i.t. VP produced scratching bouts (2.5 and 25 ng) and suppressed hindbody motor function (25 ng). The motor inhibitory effects of VP, although severe in some rats, were brief, lasting less than 15 min. In conclusion, i.t. VP produces antinociception in addition to its motor effects, and these properties appear to be due to separate mechanisms.

The dorsal raphe nucleus: a re-evaluation of its proposed role in opiate analgesia systems.

Previous studies have concluded that (a) electrical stimulation in the periaqueductal gray/dorsal raphe nucleus (PAG/DRN) region specifically produces either non-opiate or opiate forms of antinociception dependent upon the dorsoventral level of stimulation and (b) the 'opiate' form of stimulation-produced analgesia (SPA) arising from the ventral PAG/DRN region shows cross-tolerance with opiate forms of footshock analgesia, implying common neural substrates. This latter conclusion in turn implies that SPA elicited from the ventral PAG/DRN region would be expected to be antagonized by scopolamine, since this muscarinic cholinergic antagonist blocks opiate footshock analgesia. The present study demonstrates instead that neither 10 mg/kg naloxone nor 10 mg/kg scopolamine had any effect on SPA elicited from sites histologically verified to lie within the presumptive 'opiate' ventral PAG/DRN region. These data bring into question both the site specificity of opiate SPA and the common mediation of ventral PAG/DRN SPA and opiate forms of footshock analgesia.

Medial hypothalamic stimulation suppresses nociceptive spinal dorsal horn neurons but not the tail-flick reflex in the rat.

This study investigated the potential analgesic effects of medial hypothalamic stimulation (HS) on a measure of nocifensive behavior (tail-flick test (TF] in awake rats, and potential inhibitory effects of identical HS on spinal dorsal horn neuronal responses to noxious skin heating in the same animals anesthetized with sodium pentobarbital. Sixty-five male Sprague-Dawley rats implanted with a bipolar stimulation electrode in histologically verified medial hypothalamic sites were tested behaviorally for TF suppression during HS (100 ms trains at 100 Hz, 3/s, 100-1100 microA) in 2-4 consecutive weekly test sessions. Thirty-three of these rats were then used in electrophysiological experiments to record responses of 36 dorsal horn units to noxious skin heating (48-54 degrees C, 10 s/2 min) of the hindfoot pad in the absence of and during HS. Behaviorally, 31/65 rats had no TF suppression at the highest HS intensity tested (1100 microA), 24/65 rats exhibited aversive behavior or motor activity which disallowed reliable TF testing, and only 10/65 rats showed TF suppression in at least one test session. In electrophysiological experiments, the heat-evoked responses of 25/36 dorsal horn units were inhibited to at least 50% of control during HS. The responses of 11 units remained at 65-100% of the control responses during HS of up to 1100 microA. In rats demonstrating TF suppression, 4/7 units were inhibited. In rats with no TF suppression, 10/15 units were inhibited, and in rats showing aversive behavior, 11/14 units were inhibited by HS. These data indicate that although HS suppresses spinal nociceptive neurons, it does not cause reliable TF suppression in unanesthetized rats and bring into question the often-held assumption that stimulation-evoked descending inhibition of spinal nociceptive neurons implies behavioral analgesia.

Role of spinal cord neuropeptides in pain sensitivity and analgesia: thyrotropin releasing hormone and vasopressin.

The existence of a wide variety of neuropeptides within the spinal cord dorsal horn raises the question of their possible roles in sensory processing. The present series of behavioral experiments examined the effects of intrathecal (IT) administration of two such neuropeptides, thyrotropin-releasing hormone (TRH) and vasopressin (VAS), on pain sensitivity and antinociception. TRH exerted no marked effect on basal pain sensitivity over the dose range examined (0.25 ng-2.5 micrograms). However, a U-shaped dose-response effect on morphine antinociception (3 micrograms, IT) was observed, wherein potent attenuation, moderate attenuation, or enhancement of morphine-induced antinociception was observed following the various doses tested. In contrast, VAS produced non-opiate antinociception at the highest doses tested (25 ng and 250 ng) and none of the VAS doses (0.25 ng-250 ng) appeared to interact with IT morphine (3 micrograms) antinociception. Lastly, IT TRH was not observed to interact with IT VAS antinociception. These data provide evidence that these neuropeptides exert strikingly different effects on pain sensitivity and opiate antinociception, and provide initial evidence that TRH may be included in the growing list of neuropeptides that can act like endogenous opiate antagonists within the central nervous system.