Preclinical Assessment of Candidate Analgesic Drugs: Recent Advances and Future Challenges

Abstract

In analgesic drug development, preclinical procedures are widely used to assess drug effects on pain-related behaviors. These procedures share two principal components: 1) a manipulation intended to produce a pain-like state in the experimental subject and 2) measurement of behaviors presumably indicative of that pain state. Drugs can then be evaluated for their ability to attenuate pain-related behaviors. In the simplest procedures, the pain state is produced by delivery of an acute noxious stimulus (e.g., a warm thermal stimulus), and the primary dependent measures focus on withdrawal responses or other nocifensive behaviors that increase in rate, frequency, or intensity in response to the noxious stimulus. This approach has been refined in two ways. First, new methods have been developed to induce more clinically relevant pain states. In particular, pain requiring clinical intervention is often associated with inflammation or neuropathy, and novel procedures have emerged to model these conditions and their ability to produce hypersensitive pain states, such as allodynia and hyperalgesia. Second, studies are incorporating a broader array of painrelated behaviors as dependent measures. For example, pain not only stimulates nocifensive behaviors but also suppresses many adaptive behaviors, such as feeding or locomotion. Measures of pain-suppressed behaviors can provide new insights into the behavioral consequences of pain and the effects of candidate analgesics. In addition, functional magnetic resonance imaging has emerged as a noninvasive tool for investigating changes in neural activity associated with pain and analgesia. Integration of these complementary approaches may improve the predictive validity of analgesic drug development.

Anti-inflammatory, Antinociceptive Activity of an Essential Oil Recipe Consisting of the Supercritical Fluid CO2 Extract of White Pepper, Long Pepper, Cinnamon, Saffron and Myrrh in vivo

“…In each case, stimulation of the immune system causes about the release of inflammatory mediators. These mediators in turn generate numerous effects, including sustained activation and sensitization of both primary nociceptors and higher order neurons involved in the transmission of nociceptive input 45 . In this present paper, the analgesic effects of OR was assayed using the chemically and thermally induced nociceptive pain model in mice.…”

Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review

“…Models such as intradermally injected capsaicin induce hyperalgesia and allodynia [15,16]. Such models alter the peripheral and central pain system and are thought to reflect chronic pain processes to a greater extent than the acute pain models [17]. It is important to realize that experimental pain only activates part of the multidimensional mechanisms involved in pathological pain and this limits the translation of analgesic effects in experimental pain into clinical analgesic effects.…”

Electroencephalographic and convulsant effects of the delta opioid agonist SNC80 in rhesus monkeys

“…The recent development of systemically active, non-peptidic delta agonists such as BW373U86 and its O-methylated derivative SNC80 has greatly facilitated research on the physiological and behavioral consequences of delta receptor activation Calderon et al, 1994). Preclinical studies conducted with these and other related drugs suggest that delta agonists may have clinical utility as analgesics, antidepressants, cardioprotective agents, and modulators of immune function Calderon et al, 1994;Brandt et al, 2001a;Gross et al, 2004;Ossipov et al, 2004;Weber and Gomez-Flores, 2004). However, it was recognized at an early stage that piperazinyl benzamide delta agonists such as BW373U86 and SNC80 also produced convulsions in mice and rats (Comer et al, 1993;Bilsky et al, 1995;Hong et al, 1998;Broom et al, 2002a;Broom et al, 2002b;.…”