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Hybrid compounds are suggested to be a more effective remedy for treatment of various diseases than combination therapy, since the attenuation or total disappearance of side effects, typically induced by a single moiety, can be observed. This is of great importance, especially when we consider problems resulting from the use of opioid analgesics. However, although it seems that such compounds can be valuable therapeutic tools, the lack of conviction among the public as to the appropriateness of their use still remains; therefore patients are commonly treated with polypharmacy. Thus, in the presented paper we show a comparison of the antinociceptive effect between a novel opioid-neurotensin chimera called [Ile 9 ]PK20 and a mixture of its structural elements, delivered intrathecally and systemically. Additionally, motor coordination was assessed in the rotarod test. The results clearly indicate that spinal administration of the examined compounds, resulted in a long-lasting, dose- and time-dependent antinociceptive effect. Although the mixture of both pharmacophores was found to be more active than [Ile 9 ]PK20, motor impairments surfaced as a side effect. This in turn illustrates the advantageous use of hybrid structures over drug cocktails. [ABSTRACT FROM AUTHOR]

Abstract: Nucleus cuneiformis (NCF) along with periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) is a part of descending system for pain modulation. Cannabinoids have analgesic effects on the PAG and RVM. This study investigates the possible role of cannabinoids in pain modulation in the NCF. Cannabinoid agonist, WIN55,212-2 (5, 10 and 20μg/0.3μl DMSO per side), and selective cannabinoid CB1 receptor antagonist, AM251(1, 5 and 10μg/0.3μl DMSO per side), were microinjected alone or in succession. As models of acute and inflammatory pain, tail-flick and formalin test were utilized to examine the effects of these drugs on pain modulation in 5min time blocks for 60min. Results of tail-flick and formalin tests demonstrated a dose-dependent analgesic effects for WIN55,212-2, with the most significant response at the dose of 20μg/side. The analgesic responses were more effective during the first 45-min period of the tail-flick test (P <0.001) and during the late phase (P <0.001) of formalin test, compared to the early phase (P <0.05). These analgesic effects were blocked in the presence of AM251 (1μg/0.3μl DMSO per side) in both tests. Administration of AM251 alone did not have any effect on nociceptive responses in either test. The cannabinoid-mediated analgesia demonstrated in this study suggests the presence of a cannabinoid-sensitive nociceptive modulatory system in the NCF. [Copyright &y& Elsevier]

Abstract: Previous studies have demonstrated that some anticonvulsant drugs can modulate tolerance to the opioid analgesia. In the present study, the effects of lamotrigine (LTG) on the development and expression of tolerance to the morphine-induced antinociception were evaluated using tail-flick test. To assess the LTG effects on tolerance development, the animals received LTG (3, 10 or 30 mg/kg; i.p.), 30-min prior to morphine (50 mg/kg; s.c.) administration during tolerance induction period once daily for 3 days. Also, to evaluate the effects of LTG on tolerance expression, different doses of LTG were administered 30-min before challenge dose of morphine (4 mg/kg; s.c.) following morphine-induced tolerance. In each experiment the antinociceptive response to the challenge dose of morphine was evaluated before (on day 1) and after tolerance induction (on day 4) every 30-min till 2 h by tail-flick test. Furthermore, the analgesic effect of various doses of LTG alone or with the challenge dose of morphine was evaluated as well. The results showed that LTG at the doses of 10 and 30 mg/kg could inhibit the development of tolerance. Also, LTG at the dose of 30 mg/kg attenuated the expression of morphine-induced tolerance. LTG alone injection was associated significantly with higher latency period when compared to the control group. Moreover, LTG (10 and 30 mg/kg) significantly enhanced antinociceptive effect of morphine challenge dose in non-tolerant animals. These data indicated that, while LTG can attenuate both development and expression of morphine-induced tolerance, it can enhance morphine-induced antinociception. These effects may have important clinical implications. [Copyright &y& Elsevier]

The need to use anaesthetised or restrained animals in acupuncture research in laboratory animals may represent a confounding variable, since both anaesthesia and stress alter the pain threshold and the activity of pain-related brain areas. In the current study we assessed the participation of the periaqueductal gray (PAG) in electroacupuncture’s (EA) analgesic effects applied to the Zusanli point (36S) under carefully controlled stress conditions. Repeated immobilisation protocols (6 days, 1 h/day and 13 days, 2 h/day) were used to diminish the influence of acute immobilisation stress on c-Fos expression and analgesia (tail-flick test) induced by electroacupuncture on the 36S point (EA36S). Animals submitted to immobilisation alone (IMMO) or to electroacupuncture (100 Hz, 2–4 V, faradic wave) on a non-point region (EANP) were compared with animals submitted to electroacupuncture on the 36S point. In animals not previously submitted to repeated immobilisation, electroacupuncture on the 36S point induced analgesia and c-Fos expression in the PAG was not different from that induced by electroacupuncture at a non-acupuncture point. In animals submitted to repeated immobilisation (repeated immobilisation for 6 days or repeated immobilisation for 13 days), however, electroacupuncture on point 36S led to higher levels of analgesia and c-Fos expression, specifically in the ventrolateral PAG (vlPAG), as compared with animal groups subjected only to immobilisation or to electroacupuncture on a non-point. Our findings endorse previous results, and point to a specific part of the PAG involved in the effects of electroacupuncture at the Zusanli point. [Copyright &y& Elsevier]

The intracerebroventricular administration of renin substrate or angiotensin II evokes antinociception in rodents, but the brain sites where most of the renin–angiotensin system peptides act are not yet known. This study describes the antinociceptive effects of microinjecting porcine renin substrate tetradecapeptide (RS) or angiotensins I (AI), II (AII) or III (AIII) into different regions of the periaqueductal gray matter (PAG), using the rat tail flick test. All the above peptides were effective following administration into several PAG regions. Their antinociceptive effects were strongly evoked from the caudal ventrolateral and ventral PAG, including the dorsal raphe nucleus. A dose-dependent antinociception following administration into the ventrolateral PAG was demonstrated for all peptides studied. The effect of AII from the ventrolateral PAG was inhibited by the previous local administration of saralasin, a non-selective angiotensin receptor antagonist. Moreover, the peak effects of RS and AI occurred later than those of AII and AIII. The time-course of antinociception suggests that longer-chain peptides are locally processed to biologically active smaller-chain peptides. This study shows for the first time the antinociceptive effect of RS, AI, AII and III in well-defined PAG regions, an effect that is receptor mediated for AII. [Copyright &y& Elsevier]

• Intra-hippocampal SCH-23390 alleviated the LH stimulation-induced antinociception in the tail-flick test. • Blockade of D2-like receptor in the CA1 considerably decreased the antinociceptive responses in acute pain. • Contribution of D2-like receptor to pain modulation was smoothly greater than that of D1-like receptor in the CA1. • None of dopamine receptor antagonists microinjected into the CA1 changed the locomotor activity in the rats. Dopamine is the predominant catecholamine neurotransmitter in the mammalian brain which has been shown to play a critical role in antinociceptive process. Previous studies have shown that the role of CA1 region of the hippocampus in antinociception induced by stimulation of the lateral hypothalamus (LH) through the dopaminergic system in tonic pain. In this study, we tried to assess the involvement of intra-hippocampal D1- and D2-like dopamine receptors in the LH stimulation-induced antinociception during the tail-flick test as an animal model of acute pain. Ninety-five male Wistar rats were unilaterally implanted with two separate cannulae into the LH and CA1. Animals received intra-CA1 infusion of SCH-23390 (0.25, 1 and 4 µg/rat), as a D1-like dopamine receptor antagonist and sulpiride (0.125, 0.25, 1 and 4 µg/rat), as a D2-like dopamine receptor antagonist, 2 min before intra-LH administration of carbachol (250 nM/rat). The antinociceptive effects of SCH-23390 and sulpiride were measured by using a tail-flick analgesiometer and represented as the maximal possible effect (%MPE). Also, the locomotion tracking apparatus was used to measure the locomotor activity of animals. Results showed that intra-CA1 administration of SCH-23390 or sulpiride could prevent the intra-LH carbachol-induced antinociception. This effect was a little more dominant after blocking the D2-like dopamine receptor in the CA1. These findings revealed that D1- and D2-like dopamine receptors within the CA1 play an important role in antinociceptive responses induced by chemical stimulation of the LH. It could be suggested that dopamine receptors in the CA1 were triggered by LH orexinergic projections. [ABSTRACT FROM AUTHOR]