Induced Antinociceptive Activity

Result of Reported Studies Investigating the Effect of Nociceptive Sensitivity of Linalool Administration in Animals 

Effect routes Species Strain Assay Doses References 

It has been demonstrated that neuropathic pain is opioid resistant and, indeed, neither systemic nor i.t. administration of opioids reduced effectively neuropathic pain in rats (Bian et al., 1995 Lee et al., 1995 Mao et al., 1995 Ossipov et al., 1995). It seems worth to note that s.c. administration of (—) linalool attenuates mechanical allodynia in spinal nerve ligation model of neuropathic pain in mice (Levato et al., 2006). 

The peripherally acting antiallodynic/antihyperalgesic linalool may represent a promising therapeutic approach for alleviating neuropathic pain. 

This work was supported by The Science Research Promotion Fund from The Promotion and Mutual Aid of Corporation for Private Schools of Japan, a Grant-in-Aid for Science Research (C) (KAKENHI 16590058 and 17590065) from Japan Society for the Promotion of Science, and a Grant-in-Aid for High Technology Research Program from the Ministry of Education, Cultures, Sports, Science, and Technology ofjapan. We thank Makiko Akiyoshi and Maki Shigeno for expert technical assistance. 

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Martin BR. (1985). Structural requirements for cannabinoid-induced antinociceptive activity in mice. Life Sci. 36(16) 1523-30. 

The existence of further alternative transcripts of MOP was postulated by the observation that in knockout mice with disrupted exon 1, heroin but not morphine was still analgesically active. Based on earlier observations that the antagonist naloxazone blocked morphine-induced antinociception but not morphine-induced respiratory depression, a subdivision of the MOP in pi and p2 was proposed. However, no discrete mRNA for each of these MOP subtypes has been found. It is, however, possible that subtypes of MOPs result from heterodimerization with other opioid receptors or by interaction with other proteins. 

Histamine also induces antinociceptive (i.e. pain-relieving) responses in animals after microinjection into several brain regions [73, 74]. H, and H2 mechanisms are significant and both neuronal and humoral mechanisms may be involved. Brain H2 receptors appear to mediate some forms of endogenous analgesic responses, especially those elicited by exposure to stressors [75]. Many of the modulatory actions of histamine discussed above appear to be activated as part of stress responses. For reasons that remain unclear, histamine releasers, such as thioperamide, show only mild, biphasic antinociceptive actions, even though histamine is a potent and effective analgesic substance. Outside the brain, both H and H3 receptors exist on certain types of sensory nerves and activation of these receptors promotes and inhibits, respectively, peripheral nerve transmission related to pain and/or inflammation [76,77]. 

At present, BP 2.94 (36) is under clinical development in Phase II trials for the treatment of asthma, pneumoallergic diseases, and others. Preclinical studies in rodents clearly displayed anti-inflammatory as well as antinociceptive activity of BP 2.94 (36) given orally at low doses. These effects are mediated by inhibitory H3 receptors located on sensory C-fibres in several different tissues. In particular, capsaicin-induced plasma protein extravasation was dose-dependently inhibited in airways, digestive tract, skin, conjunctiva, urinaiy bladder, nasal mucosa, and dura mater of the rat. In the p-phenylbenzoquinone-induced writhing test in mice, BP 2.94 (36) had a pronounced antinociceptive activity similar to that of acetylsalicylic acid. This effect was significantly abolished by the H3 receptor antagonist thioperamide but not by naloxone. Furthermore, BP 2.94 (36) reduced zymosan-induced edema. This antiinflammatory effect was also abolished by thioperamide [6]. 

Five lignans isolated from the heartwood of T. baccata L. growing in Turkey were evaluated for their anti-inflammatory and antinociceptive activities in vivo. All of the compounds were shown to possess significant antinociceptive activities against p-bcnzoquinone-induccd abdominal contractions and significantly inhibited carrageenan-induced hind paw edema in mice [100]. 

Delta receptors nevertheless mediate some delta agonist induced analgesia, as suggested by reduced DPDPE and deltorphin activity in the DOR mutant after ITH applications [52], or enhanced antinociceptive activity in MOR mutants subjected to CFA inflammation [65]. Delta receptors also depress respiratory neurons in slice preparations [66] and mediate SNC80-evoked convulsions [67]. 

In contrast, blockade of delta2 opioid receptor by naltriben reduced RB 101 induced antinociceptive response. Thus, it could be argued that activation of deltai opioid receptors by endogenous enkephalins reduced endogenous CCK release, resulting in a decrease in CCKi receptor activation with subsequent reduction of the facilitatory effect of CCK system on opioid system, as CCKi activation seems to be essential for the potentiation of mu opioid analgesia [42,80]. 

It has been consistently and repeatedly reported that the inflammatory process is accompanied by a seemingly paradoxical enhancement of the antinociceptive activity of opioids [152], For example, carrageenan-induced inflammation elicited a 30-fold increase in the ability of morphine to inhibit evoked activity of C-fibers [153]. The antinociceptive effect of morphine was similarly enhanced in arthritic rats [154], Further, the effect of ITH DAMGO... 

The spinal antinociceptive effect of DPDPE is blocked totally by a small conductance Ca2 + -activated K + channel blocker apamin [109]. The DPDPE-induced spinal antinociception is not inhibited by a ATP-sensitive K + channel blocker glyburide [109], Like morphine, tetraethylammonium, 4-aminopyridine, and charybdotoxin are unable to block the effects of DPDPE [109], These findings suggest that the modulation of apamin-sensitive K + channels appears to play a role in the DPDPE-induced antinociception in the spinal cord. 

Figure 1 Role of ion channels in the delta opioid receptor agonist-induced spinal antinociception. Delta opioid receptor agonists acutely inhibit some neurons by increasing the conductance of an apamin-sensitive inwardly rectifying K +channel and decreasing an N-type Ca2+ channel-dependent inward current via activation of Ga and GPr These changes, induced by activation of delta opioid receptor, lead to the delta opioid receptor agonist-induced spinal antinociception.

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