Medullary pain facilitating neurons mediate allodynia in headache-related pain.

OBJECTIVE: To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia. METHODS: Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind-paws were characterized. RESULTS: IM elicited robust facial and hind-paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene-related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin-1 antagonist. Having established facial and hind-paw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM "on" cells and transient suppression of RVM "off" cells after IM. INTERPRETATION: Facial and hind-paw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia, and are consistent with a brainstem generator of allodynia associated with headache disorders.

Managing patients with local anesthetic complications using alternative methods.

This article discusses various alternative methods of treating the patient who encounters problems with local anesthetics. Those alternative methods include: acupuncture, hypnosis, sedation, general anesthesia, and antihistamines as a substitute for local anesthetics with more of a focus in using antihistamines as an effective local anesthetic agent. Although not frequently encountered in the clinical setting, allergic reactions to local anesthetics do occur. Various surveys indicate the number of deaths attributed to local anesthesia range from 1:1,500,000 to 1:4,000,000, with oral surgery offices having higher mortality rates than general dentistry offices. This occurs despite clinicians' attention to patient medical histories, aspiration of the local anesthetic syringe during injections, and minimizing the dosage of local anesthetic solutions. Generally speaking, local anesthetics can be divided into two groups: ester of benzoic and aminobenzoic derivatives (cocaine, benzocaine, procaine, tetracaine, butacaine, etc.) or amide-derivatives of xylidine and toluidine groups (lidocaine, mepivacaine, prilocaine a.k.a. Citanest, etc.). Adverse effects include allergic or toxic reactions, as well as negative effects of any vasoconstrictors contained within the local anesthetic solution. This article will concentrate on how to successfully manage patients who have previously encountered allergic reactions.

The influence of an instruction on the stimulus effects of drugs in humans.

Participants discriminated between tripelennamine and placebo in experiments differing in instructional set. In 1 experiment (SED), participants were told that 1 of the 2 drugs was more sedative-like, and during the other (STIM), 1 was more stimulant-like. During generalization tests, participants received diazepam or d-amphetamine. Percent correct was the same in both experiments. Tripelennamine increased sedative and decreased stimulant effects. Amphetamine and diazepam produced typical subjective effects. Some subjective effects differed across experiments with more sedative and less stimulant effects during SED than STIM. In SED and STIM, capsules were labeled 80% of the time as a sedative and stimulant, respectively. Thus, instructions designed to give expectations had no effect on discrimination and only a few changes in subjective effects. When asked to name the drug that they believed they received, labels reflected instructional set.

The intravenous self-administration of antihistamines by rhesus monkeys.

Rhesus monkeys were trained to lever press for infusions of cocaine during daily, 1-h experimental sessions. Following stabilization of the cocaine-maintained baselines, various antihistamines were substituted for cocaine to determine whether they would be self-administered. The results indicated that all monkeys tested self-administered tripelennamine and chlorpheniramine. One monkey out of the four self-administered pyrilamine, but only at a single (300 microgram/kg) high dose. Phenyltoloxamine, cimetidine and hydroxyzine were not self-administered. These results further illuminate differences amongst H1 antagonists in their potential for self-administration and, when examined in context with other reports, suggest that stimulant-like properties may help mediate their reinforcing effects when present.

Acute myocardial infarction associated with intravenous injection of pentazocine and tripelennamine.

This case report describes the evolution of an acute anteroseptal myocardial infarction in a 27-year-old man following intravenous injection of pentazocine and tripelennamine. Subsequent coronary angiography showed normal coronary arteries. Based on the known mechanism of action of these drugs, it is postulated that myocardial infarction resulted from coronary artery spasm secondary to excessive catecholamine stimulation.

Evaluation of some prophylactic therapies for the idiopathic headshaker syndrome.

Eighteen horses affected by the idiopathic headshaker syndrome were studied in an owner assessed trial to test the efficacy of some prophylactic therapies. Riding the affected animal with a veil over the nostrils gave varying degrees of temporary relief in three of 10 horses. Local (intra-nasal) corticosteroid therapy was reported to be slightly effective in three of nine horses, but treatment with sodium cromoglycate, systemic corticosteroid, flunixin meglumine and an antihistamine were generally ineffective. Bilateral infraorbital neurectomy provided sustained relief in three of seven horses, but in one of these cases, a reaction at the neurectomy site necessitated another surgical procedure after six months. A fourth horse was reported to be slightly improved after neurectomy. A period of nasal irritation resulting in self-inflicted trauma was a common complication of this surgery.

Enhancement of morphine-induced hyperactivity by antihistaminic drugs in mice.

Three histamine H1-receptor antagonists, chlorpheniramine, diphenhydramine and tripelennamine, were tested alone or in combination with morphine on locomotor activity in C57BL/6 mice. All three antihistaminics, at some dosage levels, slightly increased activity when given alone, but strongly enhanced morphine-induced hyperactivity. The results demonstrate that locomotor activity represents a useful test to evidence stimulatory effects of antihistaminic-opiate combinations.

Behavioral and developmental effects of prenatal exposure to pentazocine and tripelennamine combinations.

Long-Evans, hooded rats were intubated with one of four dose combinations of pentazocine and tripelennamine on Days 7-20 of pregnancy: 0:0 (mg/kg pentazocine:tripelennamine), 20:10, 40:0, or 40:20. An additional group had free access to lab chow and water throughout pregnancy. At birth, reduced body weights were evident in all drug-treated offspring. Growth deficits were not noted at 5, 10, 15 or 20 days of age. Three measures of activity were collected at 18 days of age, however, none of these measures were differentially affected as a function of prenatal treatment. At 85 days of age, offspring were tested in a two-way shuttle avoidance paradigm. Although the number of avoidances was not significantly affected by prenatal treatment, offspring exposed to these drugs in combination had shorter response latencies than controls with increased training and made more intertrial crossing responses. Additional offspring were tested for seizure susceptibility at 100 days of age. None of the parameters of seizure activity were significantly affected by prenatal drug treatment. Prenatal exposure to pentazocine and tripelennamine resulted in prenatal growth deficits, increased activity during the intertrial interval and decreased response latencies in a shuttle avoidance learning task, suggesting that this polydrug combination may be associated with some long-term behavioral teratogenic risks.

Effects of nalbuphine alone and in combination with tripelennamine on rewarding brain stimulation thresholds in the rat.

Reinforcing thresholds for rewarding brain stimulation to the medial forebrain bundle-lateral hypothalamus were determined in rats by means of a rate-free psychophysical method. Nalbuphine, a mixed agonist-antagonist opioid, alone caused a significant, but modest, dose-dependent lowering of the threshold for reinforcing stimulation. Concomitant administration of an ineffective dose of tripelennamine, an antihistamine, with nalbuphine potentiated the threshold lowering effect of nalbuphine. These results are similar to previous results obtained with tripelennamine and pentazocine suggesting that nalbuphine may have abuse potential if combined with tripelennamine.

The pharmacokinetics of pentazocine and tripelennamine.

The pharmacokinetics of single and combined doses of pentazocine HCl (40 and 80 mg) and tripelennamine HCl (50 and 100 mg) were studied in six healthy drug abusers. After intramuscular administration of 40 or 80 mg pentazocine alone, mean peak plasma concentrations at 15 minutes were 102 and 227 ng/ml, respectively, and mean plasma t1/2 values were 4.6 and 5.3 hours, respectively. After intramuscular administration of 50 or 100 mg tripelennamine, mean plasma concentrations at 30 minutes were 105 and 194 ng/ml, respectively, and mean plasma t1/2 values were 2.9 and 4.4 hours, respectively. After concurrent administration of pentazocine with tripelennamine, plasma pentazocine and tripelennamine concentrations at all time points were not significantly different from those when pentazocine or tripelennamine was administered alone. Coadministration of pentazocine and tripelennamine had no effect on the distribution, elimination, and clearance of either pentazocine or tripelennamine. In conclusion, there did not appear to be a clinically significant metabolic interaction between pentazocine and tripelennamine.

Pentazocine-tripelennamine ("T's and Blues") substitution studies in morphine-dependent rodents.

Tripelennamine, pentazocine and various pentazocine-tripelennamine combinations were tested for their ability to substitute for morphine in morphine-dependent rodents. Rats and mice were rendered physically dependent on morphine by the Drug-Admixed Food Method. Pentazocine produced a dose-related partial suppression of morphine withdrawal signs in mice, as well as in both mildly and severely dependent rats. Tripelennamine did not suppress morphine withdrawal signs, but rather aggravated them. Furthermore, tripelennamine did not potentiate the ability of pentazocine to suppress morphine withdrawal signs. It is concluded that the primary reason for the reported "street" abuse of the tripelennamine-pentazocine combinations is not related to any remarkable ability of the combination to effectively suppress the discomfort of heroin withdrawal.

Effects of pentazocine and tripelennamine on analgesia.

The analgesic effects of pentazocine and tripelennamine, alone and in combination, were assessed in rats with a hot plate apparatus. In Experiment 1, the combination of tripelennamine with chronic pentazocine produced analgesia at doses which were not analgesic when the drugs were given alone. This combination also reestablished analgesia in subjects made tolerant to pentazocine's effects. In Experiment 2, development of tolerance to the analgesic effects of pentazocine was delayed by addition of tripelennamine. These data may contribute to a rationale for the current popularity of combined pentazocine and tripelennamine abuse.

Acute bacterial endocarditis in pregnancy. A report of three cases.

Acute bacterial endocarditis, a fulminating disorder most often caused by Staphylococcus aureus, is uncommon in pregnancy. However, the frequency of this disease may be increasing due to the prevalence of intravenous drug abuse. Three cases occurred during pregnancy at Charity Hospital, New Orleans; all three patients were intravenous drug abusers. One patient had polymicrobial disease.

Evaluation of presynaptic histamine receptors in the canine renal vascular bed.

Histamine has been shown to increase renal blood flow via H1- and H2-receptors. Furthermore, H2-receptors have been demonstrated to attenuate stimulation-induced release of norepinephrine. The present studies examined whether histamine has a presynaptic effect on sympathetic nerves in the canine renal vascular bed. Renal blood flow was measured in anesthetized dogs, and vasoconstrictor responses to renal nerve stimulation and i.a. injections of norepinephrine were compared before and during i.a. infusions of histamine. Histamine increased renal blood flow and decreased stimulation-induced vasoconstriction to a greater degree than norepinephrine responses. 2-(2-pyridyl)ethylamine, an H1-agonist, did not produce consistent effects. Dimaprit, an H2-agonist, produced responses similar to histamine but to a lesser extent. The H1-antagonist tripelennamine and the H2-antagonist cimetidine each minimally antagonized the effect of histamine on nerve stimulation. When both blocking agents were infused together, maximum antagonism of histamine occurred. Thus, it appears that histamine will produce a neuroinhibitory effect in the canine renal vascular bed and this effect appears to be mediated by both H1- and H2-receptors because both receptor antagonists are necessary to block this effect.