Tony L. Sahley

Antinociceptive effects of central and systemic administrations of nicotine in the rat.

Nicotine (0.16–0.50 mg/kg, SC) was found to exert a potent antinociceptive action on thermal stimuli as measured by the tail-flick test. This antinociceptive action of nicotine could be blocked by centrally active nicotinic or muscarinic blockers implicating both classes of cholinergic receptors in this effect. Quaternary blockers, however, failed to prevent nicotine-induced antinociception. This finding, together with the ability of small doses of nicotine (25 μg) to induce potent antinociceptive effects when administered centrally, suggests a central site of action for the antinociceptive action of nicotine. The present results also support the suggestion that nicotine may selectively reduce sensitivity to certain classes of pain stimuli, perhaps through a central releasing action on acetylcholine.

Opioid blockade and social comfort in chicks

When young animals are separated from their normal social environment in groups they distress vocalize (DV) less than when isolated alone. Opioid blockade with naloxone (1 mg/kg peripherally, and 1 microgram centrally) increased crying more in group tested chicks than individually tested ones. The serotonin receptor blocking agent methysergide and the cholinergic blocking agent atropine sulfate produced similar effects. The testing of birds in mirrored environments also produced a reduction of DVs, and all three receptor blocking agents augmented DVs more in mirrored environments than in mirrorless ones. However, in studies evaluating changes in this comfort response by facilitation of opiate, serotonin (5 HT), and acetylcholine (ACh) activity (with morphine, quipazine and pilocarpine, respectively), only morphine was found to magnify the comforting effect of mirrors. The effects of naloxone on contact comfort, and the acquisition and expression of imprinting were further evaluated, and opioid blockade reduced all these measures of social comfort. It is concluded that endogenous opioid activity (and to a lesser extent, 5 HT and ACh) contribute to the comfort which animals derive from their social environment.

Brain opioids and autism: an updated analysis of possible linkages.

Considerable clinical evidence suggests that autistic children lack the normal ability or desire to engage others socially, as indicated by their poor social skills and inappropriate use of language for communicative purposes. Specifically, these children seem to lack normal amounts of social-emotional interest in other people, leading perhaps to a decreased initiative to communicate. This paper summarizes experimental evidence supporting a neurological theory, which posits that autism, at least partially, represents a disruptive overactivation of hypersensitization of neurohormone systems in the brain, such as brain opioids. These substances modulate socialemotional processes, and the possibility that blockade of opioid activity in the brain may be therapeutic for early childhood autism is discussed.

A biochemical model of peripheral tinnitus

Subjective tinnitus may be defined as the perceptual correlate of altered spontaneous neural activity occurring in the absence of an externally evoking auditory stimulus. Tinnitus can be caused or exacerbated by one or more of five forms of stress. We propose and provide evidence supporting a model that explains, but is not limited to, peripheral (cochlear) tinnitus. In this model, naturally occurring opioid dynorphins are released from lateral efferent axons into the synaptic region beneath the cochlear inner hair cells during stressful episodes. In the presence of dynorphins, the excitatory neurotransmitter glutamate, released by inner hair cells in response to stimuli or (spontaneously) in silence, is enhanced at cochlear N-methyl-D-aspartate (NMDA) receptors. This results in altered neural excitability and/or an altered discharge spectrum in (modiolar-oriented) type I neurons normally characterized by low rates of spontaneous discharge and relatively poor thresholds. It is also possible that chronic exposure to dynorphins leads to auditory neural excitotoxicity via the same receptor mechanism. Finally, the proposed excitatory interactions of dynorphins and glutamate at NMDA receptors need not be restricted to the auditory periphery.

Possible Brain Opioid Involvement in Disrupted Social Intent and Language Development of Autism

The underlying premise of this chapter is that a major dysfunction of the autistic brain resides in neural mechanisms that elaborate social motivation and thereby social intent. Although substantive understanding of brain mechanisms that mediate social emotions remains meager, animal brain research on fundamental processes such as separation distress and rough-and-tumble play has now yielded enough knowledge that some provisional hypotheses concerning the etiology and treatment of autism can be generated. Basically, our psychopharmacological work has affirmed the special importance of brain opioid activity in the elaboration of various social behaviors and social emotions, and convergent lines of reasoning suggest that opioid receptor blockade should be effective in alleviating and/or reversing the progress of certain autistic symptoms. In addition to summarizing evidence pertinent to the opioid-excess hypothesis, we discuss the possibility that certain cognitive symptoms of autism, such as problems in language development, may secondarily reflect disruption of underlying social emotions that dictate the intensity of social intent in the developing organism.

The role of brain norepinephrine in clonidine suppression of isolation-induced distress in the domestic chick

Distress vocalizations (DV) induced by social isolation were measured in 1-day-old domestic chicks after intracerebroventricular injections of drugs believed to exert their effects through the noradrenergic system. The α-adreno-receptor agonist clonidine reliably suppressed DV rates at doses low as 0.08 μg. When given alone, phentolamine, phenoxybenzamine, propranolol, sotalol, and yohimbine (adrenoreceptor antagonists) did not reliably after DV rates at doses that were not toxic. The clonidine DV suppression was reliably reversed by yohimbine (1.75 μg), but by none of the other adrenoceptor antagonists or naloxone. 6-Hydroxydopamine at doses as high as 120 μg, which essentially eliminated forebrain norepinephrine, failed to suppress DV rates reliably when given alone and, when given in combination with clonidine (0.1 μg) or morphine (0.05 μg), failed to reverse the severe DV suppression imposed by these drugs. The results suggest that clonidine suppresses DV rates in chicks through interaction with postsynaptic adrenoreceptors or by some means other than prejunctional α2-adrenoreceptor stimulation.

Effects of neonatal cerebral ventricular injection of ACTH 4–9 and subsequent adult injections on learning in male and female albino rats

An investigation of permanent developmental effects of a potent, long acting ACTH/MSH 4-10 analogue (Organon 2766) on adult passive avoidance performance and of subsequent peripheral adult injections of the same substance on visual (black and white) discrimination learning and reversal in a Thompson-Bryant box was conducted. A subproblem analysis of visual and position preferences during reversal was performed. No differences in passive avoidance performance or in original discrimination learning were obtained. Both infant and adult treatments enhanced reversal learning and visual orientation (proportion of responese to the previously positive stimulus). Infant treatment suppressed position orientation in males and enhanced position orientation in females. These effects were interpreted as indicating that ACTH-like peptides enhance attention to the relevant stimulus by a direct effect on the brain.

Cholinergic modulation of separation distress in the domestic chick

The effects of nicotine, carbachol, hexamethonium and scopolamine were investigated on distress vocalizations (DBs) of acutely isolated domestic chicks. Nicotine attenuated, while the antimuscarinic scopolamine increased the frequency of separation-induced DVs. Furthermore, the stress attenuating effects of nicotine were blocked by pretreatment with scopolamine. These results implicate muscarinic receptor participation in the control of separation-induced distress, and support the suggestion that nicotine-induced DV suppression may result from activation of behaviorally relevant muscarinic receptors via central release of acetylcholine.

Improvement in auditory function following pentazocine suggests a role for dynorphins in auditory sensitivity

The pharmacologic specificity of potentially beneficial drug effects on the auditory system were investigated. Changes in auditory sensitivity were evaluated in chinchillas following the infusion of an opioid narcotic. This drug (pentazocine) mimics endogenous opioid peptides (dynorphins), postulated to be chemical neurotransmitters (or neuro-modulators) within the mammalian cochlea. In this study, two pentazocine enantiomers were investigated over a range of stimulus intensities. Significant baseline-relative changes in compound action potential (CAP) amplitudes were observed following intravenous administration of the κopioid agonist (-)pentazocine (8 mg/kg). The σ-receptor drug agonist (+)pentazocine (8 mg/kg) produced no measurable auditory effects. The magnitude of the (-)pentazocine effects were inversely related to stimulus intensity, up to 10 dB above threshold (i.e., 10 dB SL). Consistent with the observed amplitude doubling, auditory sensitivity was also improved an average 5–7 dB sound pressure level (SPL) following the administration of (-)pentazocine, while CAP response latencies and cochlear microphonic (CM) amplitudes remained unchanged. Results indicate stereospecific κ-receptor mediated actions of pentazocine at the auditory nerve, and suggest an auditory role for neuroactive dynorphin peptides contained within the lateral efferent olivocochlear neurons.

Naloxone blockade of (-)pentazocine-induced changes in auditory function.

Objective: In a previous report, we found that intravenous (IV) (‐)pentazocine improved auditory sensitivity and significantly altered compound action potential (CAP) amplitudes. Its sigma (σ)‐receptor‐selective optical isomer (+)pentazocine administered at the same dose was without effect, suggesting that the observed auditory neural effects might be mediated by an opioid receptor. To directly test this hypothesis, in the present investigation we attempted to antagonize the auditory neural effects of(‐)pentazocine using the pure, nonspecific drug antagonist naloxone. Design: In 25 normal‐hearing, male, pigmented chinchillas, amplitude and latency changes in the click‐evoked auditory nerve CAP (N1) and cochlear microphonic (CM) were tracked at six stimulus intensities during a baseline period and after the postbaseline administration of the opioid drug agonist(‐)pentazocine (16 mg/kg; IV). In separate groups of chinchillas,(‐)pentazocine was given alone or administered in combination with the standard opioid receptor antagonist naloxone administered at two doses. Results: Robust changes in CAP amplitudes after (‐)pentazocine occurred in the absence of measurable alterations in CAP response latencies, CM amplitudes, or blood chemistries and were significantly antagonized when naloxone (5 mg/kg) was added to the IV infusion. Conclusions: The observed blockade clearly indicates that the agonist effects of(‐)pentazocine are opioid receptor‐mediated and suggests a connection between opioid receptors and auditory neural function. Mechanisms of action and the connection between an opioid modulation of auditory function and stress, hyperacusis, and tinnitus are discussed.