Effects of peptides on animal and human behavior: a review of studies published in the first twenty years of the journal Peptides.

This review catalogs effects of peptides on various aspects of animal and human behavior as published in the journal Peptides in its first twenty years. Topics covered include: activity levels, addiction behavior, ingestive behaviors, learning and memory-based behaviors, nociceptive behaviors, social and sexual behavior, and stereotyped and other behaviors. There are separate tables for these behaviors and a short introduction for each section.     

(-)-Linalool inhibits in vitro NO formation: Probable involvement in the antinociceptive activity of this monoterpene compound

Recent studies performed in our laboratory have shown that (-)-linalool, the natural occurring enantiomer in essential oils, possesses anti-inflammatory, antihyperalgesic and antinociceptive effects in different animal models. The antinociceptive and antihyperalgesic effect of (-)-linalool has been ascribed to the stimulation of the cholinergic, opioidergic and dopaminergic systems, to its local anaesthetic activity and to the blockade of N-Methyl-d-aspartate receptors (NMDA). Since nitric oxide (NO) and prostaglandin E(2) (PGE(2)) play an important role in oedema formation and hyperalgesia and nociception development, to investigate the mechanism of these actions of the (-)-linalool, we examined the effects of this compound on lipopolysaccharide (LPS)-induced responses in macrophage cell line J774.A1. Exposure of LPS-stimulated cells to (-)-linalool significantly inhibited nitrite accumulation in the culture medium without inhibiting the LPS-stimulated increase of inducible nitric oxide synthase (iNOS) expression, suggesting that the inhibitory activity of (-)-linalool is mainly due to the iNOS enzyme activity. In contrast, exposure of LPS-stimulated cells to (-)-linalool failed, if not at the highest concentration, both in inhibiting PGE(2) release and in inhibiting increase of inducible cyclooxygenase-2 (COX(2)) expression in the culture medium. Collectively, these results indicate that the reduction of NO production/release is responsible, at least partially, for the molecular mechanisms of (-)-linalool antinociceptive effect, probably through mechanisms where cholinergic and glutamatergic systems are involved.     

Spatial summation of perceived pressure,sharpness and mechanically evoked cutaneous pain

Psychophysically, spatial summation can be demonstrated as a decrease in threshold accompanying an increased field of stimulation. The present study examined to what extent different mechanically evoked percepts (pressure, sharpness, and pain) show spatial summation. Various probes were used to apply prescribed forces to the dorsal surface of the digits of 19 healthy subjects. The threshold for three perceptual qualities showed differing degrees of spatial summation: sharpness showed no statistically significant spatial summation; pain demonstrated some significant summation (46% on average); pressure showed the greatest degree of spatial summation (76% on average). The lack of significant spatial summation for sharpness threshold is consistent with the theory that perceived sharpness can be evoked by near threshold activity of a single nociceptor. The modest amount of spatial summation for pain implies that distinctly suprathreshold activation of nociceptors is required for mechanically evoked pain perception, and such input summates centrally, but not completely. The greater spatial summation observed for pressure vs. pain thresholds implies a greater degree of central summation for slowly adapting mechanoreceptors vs. nociceptors.     

Ultrastructural demonstration of synaptic connections between calcitonin gene-related peptide immunoreactive axons and dynorphin A(1–8) immunoreactive dorsal horn neurons in a rat model of peripheral inflammation and hyperalgesia

Synaptic contact between dynorphin A(1–8)-like immunoreactive lamina V spinal neurons and calcitonin gene-related peptide-like immunoreactive axon terminals was demonstrated using the immuno-electron microscopic mirror technique in a rat model of peripheral inflammation and hyperalgesia. Adjacent tissue sections were immunocytochemically labeled for either dynorphin A(1–8) or calcitonin gene-related peptide and examined at the electron microscopic level for the presence of synaptic contacts. The results suggest that some opioid neurons which exhibit a dynamic increase in dynorphin peptide associated with peripheral inflammation and hyperalgesia receive direct monosynaptic input from presumptive nociceptive primary afferents.     

Non-opioid nociceptive activity of human dynorphin mutants that cause neurodegenerative disorder spinocerebellar ataxia type 23

We previously identified four missense mutations in the prodynorphin gene that cause human neurodegenerative disorder spinocerebellar ataxia type 23 (SCA23). Three mutations substitute Leu(5), Arg(6), and Arg(9) to Ser (L5S), Trp (R6W) and Cys (R9C) in dynorphin A(1-17) (Dyn A), a peptide with both opioid activities and non-opioid neurodegenerative actions. It has been reported that Dyn A administered intrathecally (i.t.) in femtomolar doses into mice produces nociceptive behaviors consisting of hindlimb scratching along with biting and licking of the hindpaw and tail (SBL responses) through a non-opioid mechanism. We here evaluated the potential of the three mutant peptides to produce similar behaviors. Compared to the wild type (WT)-peptide, the relative potency of Dyn A R6W, L5S and R9C peptides for SBL responses was 50-, 33- and 2-fold higher, and Dyn A R6W and L5S induced the SBL responses at a 10-30-fold lower doses. Dyn A R6W was the most potent peptide. The SBL responses induced by Dyn A R6W were dose dependently inhibited by morphine (i.p.; 0.1-1 mg/kg) or MK-801, an NMDA ion channel blocker (i.t. co-administration; 5-7.5 nmol). CP-99,994, a tachykinin NK1 receptor antagonist (i.t. co-administration; 2 nmol) and naloxone (i.p.; 5 mg/kg) failed to block effects of Dyn A R6W. Thus, similarly to Dyn A WT, the SBL responses induced by Dyn A R6W may involve the NMDA receptor but are not mediated through the opioid and tachykinin NK1 receptors. Enhanced non-opioid excitatory activities of Dyn A mutants may underlie in part development of SCA23.     

Nicotinic receptor alpha7-subunits are coupled to the stimulation of nitric oxide synthase in rat dorsal root ganglion neurons

In dorsal root ganglia (DRG) intraganglionic communication takes place both among neurons and between neurons and satellite cells. One diffusible substance involved in this signalling is nitric oxide (NO), and acetylcholine (ACh) is a candidate for the stimulation of intraganglionic NO synthesis. DRG neurons react to ACh-receptor stimulation with NO-dependent cGMP production. Here, we investigated the role of the 7-subunit containing Ca²⁺-permeable nicotinic ACh receptors (nAChR) in this process. The 7-nAChR mRNA and the protein were expressed in virtually all lumbar DRG neurons as evidenced by laser-assisted cell picking and oligo cell RT-PCR, in situ hybridisation and immunohistochemistry. Strong 7-nAChR immunoreactivity was present in vanilloid receptor 1-immunoreactive, i.e. nociceptive, neurons. A neuronal production of NO in response to nicotine could be demonstrated in DRG slice preparations utilising the NO-sensitive fluorescent indicator diaminofluorescein diacetate (DAF-2DA). This stimulation of NO production was sensitive to inhibition of 7-nAChR by mecamylamine and -bungarotoxin, to inhibition of nitric oxide synthase (NOS) with L-NAME and L-NMMA, and to the blockade of voltage-operated Ca²⁺ channels by verapamil. The results show the presence of the 7-nAChR subunit in nociceptive rat DRG neurons and provide evidence for its coupling to NOS activation, indicating a role of this pathway in the intraganglionic communication in sensory ganglia.     

Contralateral but not systemic administration of bupivacaine reduces acute inflammation in the rat hindpaw

The effects of contralateral treatment with local anesthetics following acute hindpaw inflammation were investigated in rats. Inflammation was induced by unilateral injection of either 50 or 100 &#119 l of 1% carrageenan into the right paw. Contralateral injection of either bupivacaine or saline was given immediately before the carrageenan. Hindpaw edema and withdrawal responses to thermal and mechanical stimulation were evaluated after 3, 6 and 24 h. The results showed that the proinflammatory effects of carrageenan were strongest at 6 h after the injection of 100 mul carrageenan with bilaterally decreased withdrawal latencies and ipsilateral edema formation. Contralateral treatment with bupivacaine (1.25, 2.5 or 5 mg/ml) dosedependently reduced nociceptive behavior for 3-24 h. The edema was also reduced at 6 h. No effects on pain-related behavior were observed following systemic administration of bupivacaine. Sciatic nerve ligation on the contralateral side or intrathecal administration of saline significantly reduced the effects of bupivacaine when respectively compared with shamoperation and subcutaneous saline injection. Contralateral treatment with bupivacaine into the knee joint induced the same anti-nociceptive effect as administered into the paw. Our findings indicate that contralateral administration of bupivacaine induces long-lasting anti-nociceptive effects and may serve as a new or complementary treatment approach in acute inflammatory pain conditions.     

Cannabinoid CB<Subscript>2</Subscript> Receptor-Mediated Anti-nociception in Models of Acute and Chronic Pain

The endocannabinoid system consists of cannabinoid CB₁ and CB₂ receptors, endogenous ligands and their synthesising/metabolising enzymes. Cannabinoid receptors are present at key sites involved in the relay and modulation of nociceptive information. The analgesic effects of cannabinoids have been well documented. The usefulness of nonselective cannabinoid agonists can, however, be limited by psychoactive side effects associated with activation of CB₁ receptors. Following the recent evidence for CB₂ receptors existing in the nervous system and reports of their up-regulation in chronic pain states and neurodegenerative diseases, much research is now aimed at shedding light on the role of the CB₂ receptor in human disease. Recent studies have demonstrated anti-nociceptive effects of selective CB₂ receptor agonists in animal models of pain in the absence of CNS side effects. This review focuses on the analgesic potential of CB₂ receptor agonists for inflammatory, post-operative and neuropathic pain states and discusses their possible sites and mechanisms of action. Jhaveri and Sagar joint first author.     

Antinociceptive, antiedematogenic and antiangiogenic effects of benzaldehyde semicarbazone

Semicarbazones induce an anticonvulsant effect in different experimental models. As some anticonvulsant drugs also have anti-inflammatory activity, the effects of benzaldehyde semicarbazone (BS) on models of nociception, edema and angiogenesis were investigated. BS (10, 25 or 50 mg/kg, i.p.) markedly inhibited the second phase of nociceptive response induced by formaldehyde (0.34%, 20 microl) in mice, but only the highest dose inhibited the first phase of this response. The thermal hyperalgesia and mechanical allodynia induced by carrageenan (1%, 50 microl, i.pl.) in rats were also inhibited by BS (50 mg/kg, i.p.). However, treatment of mice with BS did not induce an antinociceptive effect in the hot-plate model. The paw edema induced by carrageenan (1%, 50 microl, i.pl.) in rats was inhibited by BS (25 or 50 mg/kg, i.p.). Treatment of mice with BS (0.25, 0.5 or 2.5 mg/kg/day, i.p., 7 days) also inhibited angiogenesis induced by subcutaneous implantation of a sponge disc. It is unlikely that the antinociceptive effect induced by BS results from motor incoordination or a muscle relaxing effect, as the mice treated with this drug displayed no behavioral impairment in the rotarod apparatus. In conclusion, we demonstrated that BS presents antinociceptive, antiedematogenic and antiangiogenic activities. An extensive investigation of the pharmacological actions of BS and its derivatives is justified and may lead to the development of new clinically useful drugs.